Tricyclic heteroaryl compounds useful as inhibitors of janus kinase

ABSTRACT

The present invention relates to compounds useful as inhibitors of protein kinases, particularly of JAK family kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of InternationalPatent Application No. PCT/US2007/83134 filed Oct. 31, 2007, which inturn claims the benefit, under 35 U.S.C. §111(a), of U.S. ProvisionalApplication No. 60/737,008, filed on 15 Nov. 2005, and U.S. ProvisionalApplication No. 60/738,646, filed on 21 Nov. 2005, and U.S. ProvisionalApplication No. 60/855,862, filed on 1 Nov. 2006, the entire contents ofeach of the above applications is incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of Januskinases (JAK). The invention also provides pharmaceutically acceptablecompositions that include the compounds of the invention and methods ofusing these compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

The Janus kinases (JAK) are a family of tyrosine kinases that play acritical role in cytokine signaling. The family consists of JAK-1,JAK-2, JAK-3 and TYK-2, and the down-stream substrates of this family ofkinases include the signal transducer and activator of transcription(STAT) proteins. JAK/STAT signaling has been implicated in the mediationof many abnormal immune responses, such as allergies and asthma;autoimmune diseases, such as transplant rejection, rheumatoid arthritis,amyotrophic lateral sclerosis and multiple sclerosis; as well as insolid and hematologic malignancies, such as leukemias and lymphomas.JAK-2 has also been implicated in myeloproliferative disorders, whichinclude polycythemia vera, essential thrombocythemia, chronic idiopathicmyelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloidleukemia, chronic myelomonocytic leukemia, chronic eosinophilicleukemia, hypereosinophilic syndrome, and systematic mast cell disease.

Therefore, there is a need to develop compounds that bind to the JAKfamily kinases and thereby moderate JAK/STAT signaling.

SUMMARY OF THE INVENTION

It has been found that compounds of the present invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of protein kinases, particularly the JAK family kinases.Accordingly, the invention features compounds having the formula:

or a pharmaceutically acceptable salt or prodrug thereof, where R^(A),R^(B), R^(C), R^(D), R^(E), R^(F), R^(G), R^(H), R^(K), W, X¹, X², andX³ are as defined below.

The invention also provides pharmaceutical compositions that include acompound of the invention and a pharmaceutically acceptable carrier,adjuvant, or vehicle. In addition, the invention provides methods oftreating or lessening the severity of a disease, condition, or disorderin a patient selected from: a proliferative disorder, a cardiacdisorder, a neurodegenerative disorder, an autoimmune disorder, acondition associated with organ transplant, an inflammatory disorder, animmunologically mediated disorder, or a bone disorder that includes thestep of administering to the patient a therapeutically effective dose ofa compound of the invention or a pharmaceutical composition thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions and GeneralTerminology

As used herein, the following definitions shall apply unless otherwiseindicated. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, and the Handbook of Chemistry and Physics, 75^(th) Ed. 1994.Additionally, general principles of organic chemistry are described in“Organic Chemistry,” Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5^(th) Ed.,Smith, M. B. and March, J., eds. John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted,”whether preceded by the term “optionally” or not, refers to thereplacement of one or more hydrogen radicals in a given structure with anon-hydrogen radical of a specified substituent. Unless otherwiseindicated, an optionally substituted group may have a substituent ateach substitutable position of the group. When more than one position ina given structure can be substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at each position.

As described herein, when the term “optionally substituted” precedes alist, said term refers to all of the subsequent substitutable groups inthat list. For example, if X is halogen; optionally substituted C₁₋₃alkyl or phenyl; X may be either optionally substituted alkyl oroptionally substituted phenyl. Likewise, if the term “optionallysubstituted” follows a list, said term also refers to all of thesubstitutable groups in the prior list unless otherwise indicated. Forexample: if X is halogen, C₁₋₃ alkyl, or phenyl, wherein X is optionallysubstituted by J^(X), then both C₁₋₃ alkyl and phenyl may be optionallysubstituted by J^(X). As is apparent to one having ordinary skill in theart, groups such as H, halogen, NO₂, CN, NH₂, OH, or OCF₃ would not beincluded because they arc not substitutable groups. If a substituentradical or structure is not identified or defined as “optionallysubstituted,” the substituent radical or structure is unsubstituted.

Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable,” as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, preferably, their recovery,purification, and use for one or more of the purposes disclosed herein.In some embodiments, a stable compound or chemically feasible compoundis one that is not substantially altered when kept at a temperature of40° C. or less, in the absence of moisture or other chemically reactiveconditions, for at least a week.

The term “aliphatic” or “aliphatic group,” as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 carbon atoms. In some embodiments,aliphatic groups contain 1-10 carbon atoms. In other embodiments,aliphatic groups contain 1-8 carbon atoms. In still other embodiments,aliphatic groups contain 1-6 carbon atoms, and in yet other embodiments,aliphatic groups contain 1-4 carbon atoms. Suitable aliphatic groupsinclude, but are not limited to, linear or branched, substituted orunsubstituted alkyl, alkenyl, or alkynyl groups. Further examples ofaliphatic groups include methyl, ethyl, propyl, butyl, isopropyl,isobutyl, vinyl, and sec-butyl. The terms “alkyl” and the prefix “alk-,”as used herein, are inclusive of both straight chain and branchedsaturated carbon chain. The term “alkylene,” as used herein, representsa saturated divalent hydrocarbon group derived from a straight orbranched chain saturated hydrocarbon by the removal of two hydrogenatoms, and is exemplified by methylene, ethylene, isopropylene and thelike. The term “alkenyl,” as used herein, represents monovalent straightor branched chain hydrocarbon group containing one or more carbon-carbondouble bonds. The term “alkynyl,” as used herein, represents amonovalent straight or branched chain hydrocarbon group containing oneor more carbon-carbon triple bonds.

The term “cycloaliphatic” (or “carbocycle”) refers to a monocyclic C₃-C₈hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that is completely saturatedor that contains one or more units of unsaturation, but which is notaromatic, that has a single point of attachment to the rest of themolecule, and wherein any individual ring in said bicyclic ring systemhas 3-7 members. Suitable cycloaliphatic groups include, but are notlimited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Further examplesof aliphatic groups include cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, and cycloheptenyl.

The term “heterocycle,” “heterocyclyl,” “heterocycloaliphatic,” or“heterocyclic” as used herein refers to a monocyclic, bicyclic, ortricyclic ring system in which one or more ring members are anindependently selected heteroatom and that is completely saturated orthat contains one or more units of unsaturation, but which is notaromatic, that has a single point of attachment to the rest of themolecule. In some embodiments, the “heterocycle,” “heterocyclyl,”“heterocycloaliphatic,” or “heterocyclic” group has three to fourteenring members in which one or more ring members is a heteroatomindependently selected from oxygen, sulfur, nitrogen, or phosphorus, andeach ring in the system contains 3 to 8 ring members.

Examples of heterocyclic rings include, but are not limited to, thefollowing monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino,3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino,4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl; and the followingbicycles: 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,benzodithiane, and 1,3-dihydro-imidazol-2-one.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon, including any oxidized form of nitrogen, sulfur,or phosphorus; the quaternized form of any basic nitrogen; or asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy,” or “thioalkyl,” as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl,” “haloalkenyl,” and “haloalkoxy” means alkyl,alkenyl, or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic,bicyclic, and tricyclic carbocyclic ring systems having a total of sixto fourteen ring members, wherein at least one ring in the system isaromatic, wherein each ring in the system contains 3 to 7 ring membersand that has a single point of attachment to the rest of the molecule.The term “aryl” may be used interchangeably with the term “aryl ring.”Examples of aryl rings would include phenyl, naphthyl, and anthracene.

The term “heteroaryl,” used alone or as part of a larger moiety as in“heteroaralkyl,” or “heteroarylalkoxy,” refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, wherein eachring in the system contains 3 to 7 ring members and that has a singlepoint of attachment to the rest of the molecule. The term “heteroaryl”may be used interchangeably with the term “heteroaryl ring” or the term“heteroaromatic.”

Further examples of heteroaryl rings include the following monocycles:2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl,5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g.,2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g.,2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, andthe following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl,indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl,3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

In some embodiments, an aryl (including aralkyl, aralkoxy, aryloxyalkyl,and the like) or heteroaryl (including heteroaralkyl, heteroarylalkoxy,and the like) group may contain one or more substituents. Suitablesubstituents on the unsaturated carbon atom of an aryl or heteroarylgroup include: halogen; —R^(∘); —OR^(∘); —SR^(∘); 1,2-methylenedioxy;1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R^(∘); —O(Ph)optionally substituted with R^(∘); —(CH₂)₁₋₂(Ph), optionally substitutedwith R^(∘); —CH═CH(Ph), optionally substituted with R^(∘); —NO₂; —CN;—N(R^(∘))₂; —NR^(∘)C(O)R^(∘); —NR^(∘)C(S)R^(∘); —NR^(∘)C(O)N(R^(∘))₂;—NR^(∘)C(S)N(R^(∘))₂; —NR^(∘)C(O)OR^(∘); —NR^(∘)NR^(∘)C(O)R^(∘);—NR^(∘)NR^(∘)C(O)N(R^(∘))₂; —NR^(∘)NR^(∘)C(O)OR^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(O)OR^(∘); —C(O)R^(∘); —C(S)R^(∘); —C(O)N(R^(∘))₂;—C(S)N(R^(∘))₂; —B(OR^(∘))₂; —OC(O)N(R^(∘))₂; —OC(O)R^(∘);—C(O)N(OR^(∘))R^(∘); —C(NOR^(∘))R^(∘); —S(O)₂R^(∘); —S(O)₃R^(∘);—S(O)₂N(R^(∘))₂; —S(O)R^(∘); —NR^(∘)S(O)₂N(R^(∘))₂; —NR^(∘)S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(═NH)—N(R^(∘))₂; —(CH₂)₀₋₂NHC(O)R^(∘); -L-R^(∘);-L-N(R^(∘))₂; -L-SR^(∘); -L-OR^(∘); -L-(C₃₋₁₀ cycloaliphatic), -L-(C₆₋₁₀aryl), -L-(5-10 membered heteroaryl), -L-(5-10 membered heterocyclyl),oxo, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, -L-NO₂, -L-CN, -L-OH, -L-CF₃; ortwo substituents, on the same carbon or on different carbons, togetherwith the carbon or intervening carbons to which they are bound, form a5-7 membered saturated, unsaturated, or partially saturated ring,wherein L is a C₁₋₆ alkylene group in which up to three methylene unitsare replaced by —NH—, —NR^(∘)—, —O—, —S—, —C(O)O—, —OC(O)—, —C(O)CO—,—C(O)—, —C(O)NH—, —C(O)NR^(∘)—, —C(═N—CN), —NHCO—, —NR^(∘)CO—,—NHC(O)O—, —NR^(∘)C(O)O—, —S(O)₂NH—, —S(O)₂NR^(∘)—, —NHS(O)₂—,—NR^(∘)S(O)₂—, —NHC(O)NH—, —NR^(∘)C(O)NH—, —NHC(O)NR^(∘)—,—NR^(∘)C(O)NR^(∘), —OC(O)NH—, —OC(O)NR^(∘)—, —NHS(O)₂NH—,—NR^(∘)S(O)₂NH—, —NHS(O)₂NR^(∘)—, —NR^(∘)S(O)₂NR^(∘)—, —S(O)—, or—S(O)₂—, and wherein each occurrence of R^(∘) is independently selectedfrom hydrogen, optionally substituted C₁₋₆ aliphatic, an unsubstituted5- to 6-membered heteroaryl or heterocyclic ring, phenyl, or —CH₂(Ph),or, two independent occurrences of R^(∘), on the same substituent ordifferent substituents, taken together with the atom(s) to which eachR^(∘) group is bound, form a 5-8-membered heterocyclyl, aryl, orheteroaryl ring or a 3- to 8-membered cycloalkyl ring, wherein saidheteroaryl or heterocyclyl ring has 1 to 3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. Optional substituents on thealiphatic group of R^(∘) are selected from —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic),—NO₂, —CN, —C(O)OH, —C(O)O(C₁₋₄ aliphatic), —O(haloC₁₋₄ aliphatic), orhaloC₁₋₄ aliphatic, wherein each of the foregoing C₁₋₄ aliphatic groupsof R^(∘) is unsubstituted.

In some embodiments, an aliphatic or heteroaliphatic group, or anon-aromatic heterocyclic ring may contain one or more substituents.Suitable substituents on the saturated carbon of an aliphatic orheteroaliphatic group, or of a non-aromatic heterocyclic ring areselected from those listed above for the unsaturated carbon of an arylor heteroaryl group and additionally include the following: ═O, ═S,═NNHR*, ═NN(R*)₂, ═NNHC(O)R*, ═NNHC(O)O(alkyl), ═NNHS(O)₂(alkyl), or═NR*, where each R* is independently selected from hydrogen or anoptionally substituted C₁₋₆ aliphatic. Optional substituents on thealiphatic group of R* are selected from —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic),—NO₂, —CN, —C(O)OH, —C(O)O(C₁₋₄ aliphatic), —O(halo-C₁₋₄ aliphatic), andhalo(C₁₋₄ aliphatic), where each of the foregoing C₁₋₄ aliphatic groupsof R* is unsubstituted.

In some embodiments, optional substituents on the nitrogen of anon-aromatic heterocyclic ring include —R⁺, —N(R⁺)₂, —C(O)R⁺, —C(O)OR⁺,—C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —S(O)₂R⁺, —S(O)₂N(R⁺)₂, —C(═S)N(R⁺)₂,—C(═NH)—N(R⁺)₂, or —NR⁺S(O)₂R⁺; wherein R⁺ is hydrogen, an optionallysubstituted C₁₋₆ aliphatic, optionally substituted phenyl, optionallysubstituted —O(Ph), optionally substituted —CH₂(Ph), optionallysubstituted —(CH₂)₁₋₂(Ph); optionally substituted —CH═CH(Ph); or anunsubstituted 5-6 membered heteroaryl or heterocyclic ring having one tofour heteroatoms independently selected from oxygen, nitrogen, orsulfur, or, two independent occurrences of R⁺, on the same substituentor different substituents, taken together with the atom(s) to which eachR⁺ group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroarylring or a 3-8-membered cycloalkyl ring, wherein said heteroaryl orheterocyclyl ring has 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Optional substituents on the aliphaticgroup or the phenyl ring of R⁺ are selected from —NH₂, —NH(C₁₋₄aliphatic), —N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄aliphatic), —NO₂, —CN, —C(O)OH, —C(O)O(C₁₋₄ aliphatic), —O(halo C₁₋₄aliphatic), or halo(C₁₋₄ aliphatic), wherein each of the foregoing C₁₋₄aliphatic groups of R⁺ is unsubstituted.

As detailed above, in some embodiments, two independent occurrences ofR^(∘) (or R⁺, or any other variable similarly defined herein), may betaken together with the atom(s) to which each variable is bound to forma 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-memberedcycloalkyl ring. Exemplary rings that are formed when two independentoccurrences of R^(∘) (or R⁺, or any other variable similarly definedherein) are taken together with the atom(s) to which each variable isbound include, but are not limited to the following: a) two independentoccurrences of R^(∘) (or R⁺, or any other variable similarly definedherein) that are bound to the same atom and are taken together with thatatom to form a ring, for example, N(R^(∘))₂, where both occurrences ofR^(∘) are taken together with the nitrogen atom to form apiperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) twoindependent occurrences of R^(∘) (or R⁺, or any other variable similarlydefined herein) that are bound to different atoms and are taken togetherwith both of those atoms to form a ring, for example where a phenylgroup is substituted with two occurrences of OR^(∘)

these two occurrences of R^(∘) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of R^(∘) (or R⁺, or any other variablesimilarly defined herein) are taken together with the atom(s) to whicheach variable is bound and that the examples detailed above are notintended to be limiting.

In some embodiments, an alkyl or aliphatic chain can be optionallyinterrupted with another atom or group. This means that a methylene unitof the alkyl or aliphatic chain is optionally replaced with said otheratom or group. Examples of such atoms or groups would include, but arenot limited to, —NR—, —O—, —S—, —C(O)O—, —OC(O)—, —C(O)CO—, —C(O)—,—C(O)NR—, —C(═N—CN)—, —NRCO—, —NRC(O)O—, —S(O)₂NR—, —NRS(O)₂—,—NRC(O)NR—, —OC(O)NR—, —NRS(O)₂NR—, —S(O)—, or —S(O)₂—, wherein R isdefined herein. Unless otherwise specified, the optional replacementsform a chemically stable compound. Optional interruptions can occur bothwithin the chain and at either end of the chain; i.e. both at the pointof attachment and/or also at the terminal end. Two optional replacementscan also be adjacent to each other within a chain so long as it resultsin a chemically stable compound. Unless otherwise specified, if thereplacement or interruption occurs at the terminal end, the replacementatom is bound to an H on the terminal end. For example, if —CH₂CH₂CH₃were optionally interrupted with —O—, the resulting compound could be—OCH₂CH₃, —CH₂OCH₃, or —CH₂CH₂OH.

As described herein, a bond drawn from a substituent to the center ofone ring within a multiple-ring system (as shown below), representssubstitution of the substituent at any substitutable position in any ofthe rings within the multiple ring system. For example, Figure arepresents possible substitution in any of the positions shown in Figureb.

This also applies to multiple ring systems fused to optional ringsystems (which would be represented by dotted lines). For example, inFigure c, X is an optional substituent both for ring A and ring B.

If, however, two rings in a multiple ring system each have differentsubstituents drawn from the center of each ring, then, unless otherwisespecified, each substituent only represents substitution on the ring towhich it is attached. For example, in Figure d, Y is an optionallysubstituent for ring A only, and X is an optional substituent for ring Bonly.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention.

The term “protecting group,” as used herein, represent those groupsintended to protect a functional group, such as, for example, analcohol, amine, carboxyl, carbonyl, etc., against undesirable reactionsduring synthetic procedures. Commonly used protecting groups aredisclosed in Greene and Wuts, Protective Groups In Organic Synthesis,3^(rd) Edition (John Wiley & Sons, New York, 1999), which isincorporated herein by reference. Examples of nitrogen protecting groupsinclude acyl, aroyl, or carbamyl groups such as formyl, acetyl,propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,4-nitrobenzoyl and chiral auxiliaries such as protected or unprotectedD, L or D, L-amino acids such as alanine, leucine, phenylalanine and thelike; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and thelike; carbamate forming groups such as benzyloxycarbonyl,p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike, arylalkyl groups such as benzyl, triphenylmethyl, benzyloxymethyland the like and silyl groups such as trimethylsilyl and the like.Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc)and benzyloxycarbonyl (Cbz).

The term “prodrug,” as used herein, represents a compound which istransformed in vivo into a compound of the invention. Such atransformation can be affected, for example, by hydrolysis in blood orenzymatic transformation of the prodrug form to the parent form in bloodor tissue. Prodrugs of the compounds of the invention may be, forexample, esters. Esters that may be utilized as prodrugs in the presentinvention are phenyl esters, aliphatic (C₁-C₂₄) esters, acyloxymethylesters, carbonates, carbamates, and amino acid esters. For example, acompound of the invention that contains an OH group may be acylated atthis position in its prodrug form. Other prodrug forms includephosphates, such as, for example those phosphates resulting from thephosphonation of an OH group on the parent compound. A thoroughdiscussion of prodrugs is provided in T. Higuchi and V. Stella,Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. SymposiumSeries, Edward B. Roche, ed., Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press, 1987, andJudkins et al., Synthetic Communications 26(23):4351-4367, 1996, each ofwhich is incorporated herein by reference.

Unless otherwise stated, all tautomeric forms of the compounds of theinvention are within the scope of the invention. Additionally, unlessotherwise stated, structures depicted herein are also meant to includecompounds that differ only in the presence of one or more isotopicallyenriched atoms. For example, compounds having the present structuresexcept for the replacement of hydrogen by deuterium or tritium, or thereplacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within thescope of this invention. Such compounds are useful, for example, asanalytical tools or probes in biological assays.

Description of Compounds of the Invention

In one aspect, the present invention features compounds having theformula:

wherein

-   W is —N(R^(F))—, —C(X)N(R^(F))— or —N(R^(F))C(X)—;-   X is O, S, [hydrogen, hydrogen] or [hydrogen, R];-   X² is N or C—R^(X2), wherein R^(X2) is hydrogen, halogen, —CN, —NO₂,    —OR^(X2B), —OC(O)R^(X2B), —OC(O)OR^(X2B), —OC(O)NR^(X2A)R^(X2B),    OC(S)R^(X2B), —SR^(X2B), —SC(O)R^(X2B), —SC(S)R^(X2B),    —C(O)OR^(X2B), —C(O)NR^(X2A)R^(X2B), —C(S)NR^(X2A)R^(X2B),    —NR^(X2A)R^(X2B), —S(O)R^(X2B)R^(X2B), —S(O)₂R^(X2B),    —S(O)₂NR^(X2A)R^(X2B), C₁₋₄ haloaliphatic, optionally substituted    C₃₋₈ cycloaliphatic, C₁₋₆ aliphatic;-   X⁴ is N or C—R^(B4), X⁵ is N or C—R^(B5), X⁶ is N or C—R^(B6), and    X⁷ is N or C—R^(B7), where optionally up to two of X⁴, X⁵, X⁶, and    X⁷ are N and each of R^(B4), R^(B5), R^(B6), and R^(B7) is,    independently, hydrogen, halogen, —CN, —NO₂, —OR, —OC(O)R, —OC(O)OR,    —OC(O)NRR, —OC(S)R, —SR, —SC(O)R, —SC(S)R, —C(O)OR, —C(O)NRR,    —C(S)NRR, —NRR, —S(O)R, —S(O)₂R, —S(O)₂NRR, optionally substituted    C₁₋₄ haloaliphatic, C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl,    3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic    heterocyclyl, or 5- to 8-membered monocyclic heteroaryl, 8- to    12-membered bicyclic heteroaryl;-   each of R^(F) and R^(G) is, independently, hydrogen, optionally    substituted C₁₋₆ aliphatic, C₁₋₄ haloaliphatic, C₃₋₈ cycloaliphatic,    C₆₋₁₀ aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to    12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic    heteroaryl, 8- to 12-membered bicyclic heteroaryl, or when W is    N(R^(F)), R^(F) and R^(G) and the intervening atoms together    optionally form a N═C bond;-   R^(H) is hydrogen, optionally substituted C₁₋₆ aliphatic, C₁₋₄    haloaliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl, 3- to 8-membered    monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5-    to 8-membered monocyclic heteroaryl, or 8- to 12-membered bicyclic    heteroaryl;-   R^(X2A) is hydrogen, optionally substituted C₁₋₆ aliphatic, C₃₋₈    cycloaliphatic, C₆₋₁₀ aryl, 3- to 8-membered monocyclic    heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to    8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic    heteroaryl, —C(O)R, —C(O)NRR, —C(O)OR, —S(O)R, —S(O)₂R, or    —S(O)₂NRR;-   each of R, R, and R^(X2B) is, independently, hydrogen, optionally    substituted C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl, 3- to    8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic    heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to    12-membered bicyclic heteroaryl;-   each of said heterocyclyl and heteroaryl rings contains one to four    heteroatoms independently selected from oxygen, sulfur, or nitrogen;-   the optional substituents on one or more carbon atoms of each of    said aryl and heteroaryl groups are: halogen; —R^(∘); —OR^(∘);    —SR^(∘); 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl optionally    substituted with R^(∘); —O(Ph) optionally substituted with R^(∘);    —(CH₂)₁₋₂(Ph) optionally substituted with R^(∘); —CH═CH(Ph)    optionally substituted with R^(∘); —NO₂; —CN; —N(R^(∘))₂;    —NR^(∘)C(O)R^(∘); —NR^(∘)C(S)R^(∘); —NR^(∘)C(O)N(R^(∘))₂;    —NR^(∘)C(S)N(R^(∘))₂; —NR^(∘)C(O)OR^(∘); —NR^(∘)NR^(∘)C(O)R^(∘);    —NR^(∘)NR^(∘)C(O)N(R^(∘))₂; —NR^(∘)NR^(∘)C(O)OR^(∘); —C(O)C(O)R^(∘);    —C(O)CH₂C(O)R^(∘); —C(O)OR^(∘); —C(O)R^(∘); —C(S)R^(∘);    —C(O)N(R^(∘))₂; —C(S)N(R^(∘))₂; —B(OR^(∘))₂, —OC(O)N(R^(∘))₂;    —OC(O)R^(∘); —C(O)N(OR^(∘))R^(∘); —C(═NOR^(∘))R^(∘); —S(O)₂R^(∘);    —S(O)₂OR^(∘); —S(O)₂N(R^(∘))₂; —S(O)R^(∘); —NR^(∘)S(O)₂N(R^(∘))₂;    —NR^(∘)S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(═NH)—N(R^(∘))₂; or    —(CH₂)₀₋₂NHC(O)R^(∘); -L-R^(∘); -L-N(R^(∘))₂; -L-SR^(∘); -L-OR^(∘);    -L-(C₃₋₁₀ cycloaliphatic), -L-(C₆₋₁₀ aryl), -L-(5-10 membered    heteroaryl), -L-(5-10 membered heterocyclyl), oxo, C₁₋₄ haloalkoxy,    C₁₋₄ haloalkyl, -L-NO₂, -L-CN, -L-OH, -L-CF₃; or two substituents,    on the same carbon or on different carbons, together with the carbon    or intervening carbons to which they are bound, form a 5-7 membered    saturated, unsaturated, or partially saturated ring, wherein L is a    C₁₋₆ alkylene group in which up to three methylene units are    replaced by —NH—, —NR^(∘)—, —O—, —S—, —C(O)O—, —OC(O)—, —C(O)C(O)—,    —C(O)—, —C(O)NH—, —C(O)NR^(∘)—, —C(═N—CN)—, —NHC(O)—, —NR^(∘)C(O)—,    —NHC(O)O—, —NR^(∘)C(O)O—, —S(O)₂NH—, —S(O)₂NR^(∘)—, —NHS(O)₂—,    —NR^(∘)S(O)₂—, —NHC(O)NH—, —NR^(∘)C(O)NH—, —NHC(O)NR^(∘)—,    —NR^(∘)C(O)NR^(∘), —OC(O)NH—, —OC(O)NR^(∘)—, —NHS(O)₂NH—,    —NR^(∘)S(O)₂NH—, —NHS(O)₂NR^(∘)—, —NR^(∘)S(O)₂NR^(∘)—, —S(O)—, or    —S(O)₂—, and wherein each occurrence of R^(∘) is independently    selected from hydrogen, optionally substituted C₁₋₆ aliphatic, an    unsubstituted 5- to 6-membered heteroaryl or heterocyclic ring,    phenyl, or —CH₂(Ph), or, two independent occurrences of R^(∘), on    the same substituent or different substituents, taken together with    the atom(s) to which each R^(∘) group is bound, form a 5-8-membered    heterocyclyl, aryl, or heteroaryl ring or a 3- to 8-membered    cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1    to 3 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, wherein optional substituents on the aliphatic group of    R^(∘) are selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄    aliphatic)₂, halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic), —NO₂,    —CN, —C(O)OH, C(O)O(C₁₋₄ aliphatic), O(haloC₁₋₄ aliphatic), or    haloC₁₋₄ aliphatic, wherein each of the C₁₋₄ aliphatic groups of    R^(∘) is unsubstituted; and-   the optional substituents on one or more carbon atoms of each of    said aliphatic, haloaliphatic, cyclo aliphatic, and heterocyclyl    groups are as defined for said aryl and heteroaryl groups and    additionally comprise: ═O, ═S, ═NNHR*, ═NN(R*)₂, ═NNHC(O)R*,    ═NNHC(O)O(alkyl), ═NNHS(O)₂(alkyl), or ═NR*, wherein each R* is    independently selected from hydrogen or an optionally substituted    C₁₋₆ aliphatic, and where optional substituents on said aliphatic    group of R* are selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄    aliphatic)₂, halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic), —NO₂,    —CN, —C(O)OH, —C(O)O(C₁₋₄ aliphatic), —O(halo-C₁₋₄ aliphatic), and    halo(C₁₋₄ aliphatic), wherein each of the foregoing C₁₋₄ aliphatic    groups of R* is unsubstituted.

In one embodiment, a compound of formula I-a has the formula:

whereineach of R^(II2), R^(II3), R^(II4), R^(II5), and R^(II6) is,independently, hydrogen, halogen, —CN, —NO₂, —OR, —B(OR)₂, —OC(O)R,—OC(O)OR, —OC(S)R, —SR, —SC(O)R, —SC(S)R, —C(O)OR, —C(O)NRR, —C(S)NRR,—NRR, —S(O)R, —S(O)₂R, —S(O)₂NRR, optionally substituted C₁₋₄haloaliphatic, C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl, 3- to8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclicheterocyclyl, or 5- to 8-membered monocyclic heteroaryl, 8- to12-membered bicyclic heteroaryl. In a further embodiment, R^(H4) is —OR,—B(OR)₂, —OC(O)R, —OC(O)OR, or —OC(S)R; each of R^(B4), R^(B5), andR^(B6) is hydrogen; and X² is N or C—H. Desirably, R^(H4) is —OH. Inanother further embodiment, one or both of R^(H3) and R^(H5) is ahalogen. In yet another example, both of R^(H3) and R^(H5) is a halogen,such as, for example, fluorine.

In another embodiment of a compound of formula I-a, W is —N(R^(F))—. Inanother embodiment, at least one of R^(G) or R^(H) is not hydrogen. In afurther embodiment, R^(H) is an optionally substituted C₁₋₆ aliphatic,C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl, 3- to 8-membered monocyclicheterocyclyl, or 5- to 8-membered monocyclic heteroaryl. Further still,R^(H) is an optionally substituted C₆₋₁₀ aryl or 5- to 8-memberedmonocyclic heteroaryl.

In yet another embodiment of a compound of formula I-a, or apharmaceutically acceptable salt thereof, the compound has the formula:

whereineach of R^(H2), R^(H3), R^(H4), R^(H5), and R^(H6) is, independently,hydrogen, halogen, —CN, —NO₂, —OR, —B(OR)₂, —OC(O)R, —OC(O)OR, —OC(S)R,—SR, —SC(O)R, —SC(S)R, —C(O)OR, —C(O)NRR, —C(S)NRR, —NRR, —S(O)R,—S(O)₂R, —S(O)₂NRR, optionally substituted C₁₋₄ haloaliphatic, C₁₋₆aliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl, 3- to 8-membered monocyclicheterocyclyl, 8- to 12-membered bicyclic heterocyclyl, or 5- to8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl.

In a further embodiment of compounds of formula II-a, R^(H4) is —OR,—B(OR)₂, —OC(O)R, —OC(O)OR, or —OC(S)R; each of R^(B4), R^(B5), andR^(B6) is hydrogen; and X² is N or C—H. Further still, in anotherembodiment, R^(H4) is —OH.

In another embodiment, compounds of formula I-a have the formula:

In a further embodiment of compounds of formula II-f or II-g, each ofR^(B4), R^(B5), R^(B6) and R^(B7) is hydrogen.

In another embodiment for any of the compounds of the invention, each ofR^(B4), R^(B5), and R^(B6) is hydrogen; X⁷ is N or C—H; X² is N or C—H;and each of R^(H2), R^(H3), R^(H5), and R^(H6) is, independently,hydrogen, halogen, —CN, —NO₂, —OR, —B(OR)₂, —OC(O)R, —OC(O)OR, —C(O)OR,—C(O)NRR, —C(S)NRR, —NRR, —S(O)₂R, —S(O)₂NRR, optionally substitutedC₁₋₄ haloaliphatic, C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, wherein each ofR and R is, independently, hydrogen or optionally substituted C₁₋₆aliphatic.

In another aspect, the invention features a compound selected from thegroup of compounds listed in Table 1.

JAK-2 and JAK-3 inhibition assays were performed as described elsewhereherein. Table 1 presents enzyme inhibition data for certain exemplarycompounds, where “A” represents a K_(i) of 0.25 μM or less, “B”represents a K_(i) of greater than 0.25 μM and less than or equal to 2.5and “C” represents a K_(i) value of greater than 2.5 μM.

TABLE 1 JAK- JAK- Structure 2 3

1 C B

2 C C

3 C B

4 C C

5 B B

6 B B

7 A B

8 B B

9 B B

10 C C

11 A B

12 B B

13 B B

14 B B

15 C C

16 B C

17 B B

18 A B

19 B B

20 B B

21 B B

22 A B

23 B B

24 B B

25 A B

26 A B

27 A A

28 B B

29 B B

30 A A

31 A B

32 B C

33 B B

34 B B

35 B B

36 B B

37 C C

38 B B

39 A B

40 B B

41 B C

42 B B

43 B C

44 A B

45 A B

46 A A

47 B B

48 B B

49 A B

50 B C

51 B B

52 B B

53 A A

54 A B

55 A A

56 A A

57 A A

58 B B

59 B C

60 B C

61 A A

62 A A

63 A A

64 A A

65 A A

66 A A

67 A A

68 A A

69 A A

70 A B

71 A A

72 C B

73 A A

74 A A

75 A A

76 A A

77 A A

78 B B

79 B B

80 C C

81 A A

82 A A

83 A A

84 A A

85 B B

86 C C

87 C C

88 C C

89 B C

90 B B

91 C C

92 A A

93 A A

94 A A

95 A A

96 A B

97 A A

98 A B

99 C B

100 C B

101 C C

102 C C

103 A A

104 B B

105 A A

106 A A

107 A A

108 C C

109 B B

110 C C

111 C C

112 A A

113 A A

114 B B

115 A A

116 A A

117 A A

118 A A

119 B B

120 C C

121 C C

122 C C

123 B C

124 B B

125 A A

126 C C

127 A B

128 A A

129 C C

130 A B

131 A B

132 C C

133 A A

134 B B

135 A A

136 C C

137 B C

138 C C

139 B B

140 A A

141 A B

142 C C

143 C C

144 B C

145 A B

146 A A

147 C C

148 B B

149 B C

150 A A

151 B B

152 C C

153 C C

154 A A

155 A A

156 B B

157 A A

158 A A

159 A A

160 A A

161 A B

162 B B

In another aspect, the invention features a process for the preparationof a compound having the formula:

where X², X⁴, X⁵, X⁶, X⁷, R^(F), R^(G), and R^(H) are as defined abovefor a compound of formula I-a. The process includes the following steps:(a) reacting a compound having the formula:

with a compound having the formula:

where Z is Cl, Br, I, —OP(O)(OR)₂, —OTs, or —OTf; M is —B(OR)₂, —SnR₃,—SiR₃, —ZnR₂, —Mg-Hal, —Zn-Hal, —Cu-Hal, —ZrCp₂Hal, or —AlR₂, where eachR is, independently, C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, or C₆₋₁₀ aryl;and P is a protecting group, to produce a compound having the formula:

(b) removing protecting group P to produce a compound having theformula:

and(c) reacting the compound of formula V-a with a compound having theformula:

under acidic conditions to produce the compound of formula II-b.

In one embodiment, the compound of formula II-b has the formula:

In another aspect, the invention features a process for the preparationof a compound of having the formula:

where X², X⁴, X⁵, X⁶, X⁷, R^(F) and R^(H) are as defined above for acompound of formula I-a. The process includes the following steps:

-   (a) reacting a compound having the formula:

with a compound having the formula:

wherein

Z is, Cl, Br, I, —OP(O)(OR)₂, —OTs, or —OTf and M is —B(OR)₂, —SnR₃,—SiR₃, —ZnR₂,

—Mg-Hal, —Zn-Hal, —CuHal, —ZrCp₂Hal, or —AlR₂, where each R is,independently, C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, or C₆₋₁₀ aryl, toproduce a compound having the formula:

-   (b) subjecting said compound of formula V-b to dehydration    conditions to produce an intermediate having the formula:

and

-   (c) reacting said intermediate of formula II-c with a reducing agent    to produce said compound having formula II-d.

In one embodiment, each of X², X⁴, X⁵, X⁶, X⁷ is C—H.

In one example, the process provides a compound of formula II-d havingthe formula:

In another example, R^(F) is hydrogen and step (c) is not performed,such that the process produces a compound having the formula:

For compounds of formulae II-f and II-g, R^(B4), R^(B5), R^(B6), andR^(B7) is as defined for a compound of formula I-a. In one embodiment,X² is C—H and each of R^(B4), R^(B5), R^(B6), and R^(B7) is hydrogen.

Compositions, Formulations, and Administration of Compounds of theInvention

The invention also provides pharmaceutical compositions that include acompound of the invention and a pharmaceutically acceptable carrier,adjuvant, or vehicle. In one embodiment, the composition furtherincludes a therapeutic agent selected from: a chemotherapeutic oranti-proliferative agent, an anti-inflammatory agent, animmunomodulatory or immunosuppressive agent, a neurotrophic factor, anagent for treating cardiovascular disease, an agent for treatingdestructive bone disorders, an agent for treating liver disease, ananti-viral agent, an agent for treating blood disorders, an agent fortreating diabetes, or an agent for treating immunodeficiency disorders.Desirably, the therapeutic agent is an immunomodulatory orimmunosuppressive agent.

The invention also features the use of a compound of the invention, or apharmaceutical composition thereof, for treating or lessening theseverity of a disease, condition, or disorder in a patient selectedfrom: a proliferative disorder, a cardiac disorder, a neurodegenerativedisorder, an autoimmune disorder, a condition associated with organtransplant, an inflammatory disorder, an immunologically mediateddisorder, or a bone disorder. The use includes the step of administeringto the patient a therapeutically effective dose of a compound of theinvention, or a pharmaceutical composition thereof. In one embodiment,the use further includes a step of administering to the patient anadditional therapeutic agent selected from: a chemotherapeutic oranti-proliferative agent, an anti-inflammatory agent, animmunomodulatory or immunosuppressive agent, an agent for treatingcardiovascular disease, an agent for treating destructive bonedisorders, an agent for treating blood disorders, an agent for treatingdiabetes, or an agent for treating immunodeficiency disorders, in whichthe additional therapeutic agent is appropriate for the disease beingtreated and the additional therapeutic agent is administered togetherwith a compound or composition of the invention as a single dosage formformulation or separately from a compound or composition of theinvention as part of a multiple dosage form formulation.

In an embodiment of any treatment method of the invention, the disease,condition, or disorder is allergy, asthma, chronic obstructive pulmonarydisease (COPD), diabetes, osteoarthritis, rheumatoid arthritis,Alzheimer's disease, Huntington's disease, Parkinson's disease,AIDS-associated dementia, amyotrophic lateral sclerosis (AML), multiplesclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, perivascularfibrosis, benign prostatic hyperplasia, vascular smooth muscle cellproliferation, endothelial dysfunction, ischemia/reperfusion-inducedinjury, stroke, baldness, cancer, malignoma, hepatomegaly, hypertension,cardiovascular disease, cardiomegaly, cystic fibrosis, restenosis,psoriasis, inflammation, hypertension, angina pectoris, cerebrovascularcontraction, peripheral circulation disorder, premature birth, pretermlabor, atherosclerosis, vasospasm, cerebral vasospasm, coronaryvasospasm, retinopathy, neurite outgrowth, glaucoma, erectiledysfunction (ED), AIDS, a respiratory syncytial viral (RSV) infection,osteoporosis, Crohn's Disease, colitis, or Raynaud's Disease. Desirably,the disease, condition, or disorder is atherosclerosis, hypertension,multiple sclerosis, erectile dysfunction, ischemia/reperfusion-inducedinjury, stroke, cerebral vasospasm, coronary vasospasm, cardiachypertrophy, or glaucoma. Most desirably, the disease, disorder, orcondition is asthma or transplant rejection.

The invention also features a method of measurably inhibiting JAK kinaseactivity in a biological sample that includes contacting the biologicalsample with a compound of the invention, or a pharmaceutical compositionthereof.

The amount of compound in a composition of this invention is such thatit measurably inhibits a protein kinase, such as, for example, a JAKfamily kinase, in a biological sample or in a patient. The term“measurably inhibit,” as used herein means a measurable change in kinaseactivity, particularly JAK family activity, between a sample comprisinga compound of this invention and a JAK kinase and an equivalent samplecomprising JAK kinase, respectively, in the absence of said compound.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable prodrugs, salts,esters, salts of such esters, or any other adduct or derivative whichupon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitory active metabolite or residuethereof. As used herein, the term “inhibitory active metabolite orresidue thereof” means that a metabolite or residue thereof is also aninhibitor of a JAK family kinase.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 66:1-19, 1977, which isincorporated herein by reference. Pharmaceutically acceptable salts ofthe compounds of this invention include those derived from suitableinorganic and organic acids and bases. Examples of pharmaceuticallyacceptable, nontoxic acid addition salts are salts of an amino groupformed with inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid and perchloric acid or with organic acidssuch as acetic acid, oxalic acid, maleic acid, tartaric acid, citricacid, succinic acid or malonic acid or by using other methods used inthe art such as ion exchange. Other pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconatc, dodecylsulfatc,ethanesulfonatc, formate, fumaratc, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethan esulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, C₁₋₈ sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. In Remington: TheScience and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy,Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia ofPharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan,1988-1999, Marcel Dekker, New York, the contents of each of which isincorporated by reference herein, are disclosed various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal, intraocular,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils arc conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

The pharmaceutically acceptable compositions of this invention may beorally administered in any orally acceptable dosage form including, butnot limited to, capsules, tablets, aqueous suspensions or solutions. Inthe case of tablets for oral use, carriers commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

The pharmaceutically acceptable compositions of this invention may alsobe administered topically, especially when the target of treatmentincludes areas or organs readily accessible by topical application,including diseases of the eye, the skin, or the lower intestinal tract.Suitable topical formulations are readily prepared for each of theseareas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutically acceptable compositionsmay be formulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutically acceptable compositions canbe formulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may beformulated, e.g., as micronized suspensions in isotonic, pH adjustedsterile saline or other aqueous solution, or, preferably, as solutionsin isotonic, pH adjusted sterile saline or other aqueous solution,either with or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutically acceptablecompositions may be formulated in an ointment such as petrolatum. Thepharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of thisinvention are formulated for oral administration.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microcmulsions that arc compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The compounds of the invention are preferably formulated in dosage unitform for ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts.

The amount of the compounds of the present invention that may becombined with the carrier materials to produce a composition in a singledosage form will vary depending upon the host treated, the particularmode of administration. Preferably, the compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe inhibitor can be administered to a patient receiving thesecompositions.

Depending upon the particular condition, or disease, to be treated orprevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may also be present inthe compositions of this invention. As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease, or condition, are known as “appropriate for thedisease, or condition, being treated.”

For example, chemotherapeutic agents or other anti-proliferative agentsmay be combined with the compounds of this invention to treatproliferative diseases and cancer. Examples of known chemotherapeuticagents include, but are not limited to, Gleevec™, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, and platinum derivatives.

Other examples of agents the inhibitors of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for Parkinson'sDisease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole,bromocriptine, pergolide, trihexephendyl, and amantadine; agents fortreating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex®and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such asalbuterol and Singulair®; agents for treating schizophrenia such aszyprcxa, risperdal, seroquel, and haloperidol; anti-inflammatory agentssuch as corticosteroids, TNF blockers, TL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

Uses of the Compounds and Compositions of the Invention

A compound or composition of the invention can be used as a monotheraphyto treat or lessen the severity of a disease, condition or disorder in apatient selected from: a proliferative disorder, a cardiac disorder, aneurodegenerative disorder, a psychotic disorder, an autoimmunedisorder, a condition associated with organ transplant, an inflammatorydisorder, an immunologically-mediated disorder, a viral disease, or abone disorder by administering to the patient a compound or acomposition of the invention in an effective amount.

The treatment method can further include the additional step ofadministering to the patient an additional therapeutic agent(combination therapy) selected from: a chemotherapeutic oranti-proliferative agent, an anti-inflammatory agent, animmunomodulatory or immunosuppressive agent, a neurotrophic factor, ananti-psychotic agent, an agent for treating cardiovascular disease, anagent for treating destructive bone disorders, an agent for treatingliver disease, an anti-viral agent, an agent for treating blooddisorders, an agent for treating diabetes, or an agent for treatingimmunodeficiency disorders, wherein the additional therapeutic agent isappropriate for the disease being treated and the additional therapeuticagent is administered together with a compound or composition of theinvention as a single dosage form or separately from the compound orcomposition as part of a multiple dosage form.

Diseases, conditions, or disorders that can be so treated by monotherapyor combination therapy include allergy, asthma, chronic obstructivepulmonary disease (COPD), diabetes, osteoarthritis, rheumatoidarthritis, Alzheimer's disease, Huntington's disease, Parkinson'sdisease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML),multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy,perivascular fibrosis, benign prostatic hyperplasia, vascular smoothmuscle cell proliferation, endothelial dysfunction,ischemia/reperfusion-induced injury, stroke, baldness, cancer,malignoma, hepatomegaly, hypertension, cardiovascular disease,cardiomegaly, cystic fibrosis, restenosis, psoriasis, inflammation,hypertension, angina pectoris, cerebrovascular contraction, peripheralcirculation disorder, premature birth, preterm labor, atherosclerosis,vasospasm, cerebral vasospasm, coronary vasospasm, retinopathy, neuriteoutgrowth, glaucoma, erectile dysfunction (ED), AIDS, a respiratorysyncytial viral (RSV) infection, osteoporosis, Crohn's Disease, colitis,or Raynaud's Disease.

In some embodiments, the present invention relates to a method fortreating or lessening the severity of a cancer. In further embodiments,the present invention relates to a method for treating or lessening theseverity of a cancer selected from brain (gliomas), breast, colon, headand neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate,sarcoma, or thyroid. In yet further embodiments, the present inventionrelates to a method for treating or lessening the severity ofpancreatic, prostate, or ovarian cancer.

The invention provides a method of inhibiting JAK kinase activity in abiological sample that includes contacting the biological sample with acompound or composition of the invention. The term “biological sample,”as used herein, means a sample outside a living organism and includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.Inhibition of kinase activity, particularly JAK kinase activity, in abiological sample is useful for a variety of purposes known to one ofskill in the art. Examples of such purposes include, but are not limitedto, biological specimen storage and biological assays. Inhibition of JAKkinase activity in a biological sample does not relate to therapeuticmethods, such as, for example, blood transfusions or organtransplantations.

The invention also provides a method of inhibiting JAK kinase activityin a patient, comprising administering to the patient a compound orcomposition of the invention. In an embodiment, the invention comprisesa method of treating or lessening the severity of a JAK-mediatedcondition or disease in a patient. The term “JAK-mediated disease,” asused herein, means any disease or other deleterious condition in which aJAK family kinase, in particular JAK-2 or JAK-3, is known to play arole. Such conditions include, without limitation, immune responses suchas allergic or type I hypersensitivity reactions, asthma, autoimmunediseases such as transplant rejection, graft versus host disease,rheumatoid arthritis, amyotrophic lateral sclerosis, and multiplesclerosis, neurodegenerative disorders such as familial amyotrophiclateral sclerosis (FALS), as well as in solid and hematologicmalignancies such as leukemias and lymphomas.

A compound or composition of the invention may also be used to treat amyeloproliferative disorder. In one embodiment, the myeloproliferativedisorder is polycythemia vera, essential thrombocythemia, or chronicidiopathic myelofibrosis. In another embodiment, the myeloproliferativedisorder is myeloid metaplasia with myelofibrosis, chronic myeloidleukemia (CML), chronic myelomonocytic leukemia, chronic eosinophilicleukemia, hypereosinophilic syndrome, systematic mast cell disease,atypical CML, or juvenile myelomonocytic leukemia.

In certain embodiments of the present invention an “effective amount” or“effective dose” of the compound or pharmaceutically acceptablecomposition is that amount effective for treating or lessening theseverity of one or more of the aforementioned disorders. The compoundsand compositions, according to the method of the present invention, maybe administered using any amount and any route of administrationeffective for treating or lessening the severity of the disorder ordisease. The exact amount required will vary from subject to subject,depending on the species, age, and general condition of the subject, theseverity of the infection, the particular agent, its mode ofadministration, and the like. A compound or composition can also beadministered with one or more other therapeutic agents, as discussedabove.

The compounds of this invention or pharmaceutical compositions thereofmay also be used for coating an implantable medical device, such asprostheses, artificial valves, vascular grafts, stents and catheters.Vascular stents, for example, have been used to overcome restenosis(re-narrowing of the vessel wall after injury). However, patients usingstents or other implantable devices risk clot formation or plateletactivation. These unwanted effects may be prevented or mitigated bypre-coating the device with a pharmaceutically acceptable compositioncomprising a compound of this invention.

Suitable coatings and the general preparation of coated implantabledevices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and5,304,121, the contents of each of which are incorporated by referenceherein. The coatings are typically biocompatible polymeric materialssuch as a hydrogel polymer, polymethyldisiloxane, polycaprolactone,polyethylene glycol, polylactic acid, ethylene vinyl acetate, andmixtures thereof. The coatings may optionally be further covered by asuitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol,phospholipids or combinations thereof to impart controlled releasecharacteristics into the composition. Implantable devices coated with acompound of this invention are another embodiment of the presentinvention. The compounds may also be coated on implantable medicaldevices, such as beads, or co-formulated with a polymer or othermolecule, to provide a “drug depot,” thus permitting the drug to bereleased over a longer time period than administration of an aqueoussolution of the drug.

PREPARATION OF THE COMPOUNDS OF THE INVENTION

The following definitions describe terms and abbreviations used herein:

-   ATP adenosine triphosphate-   Boc t-butoxyl carbonyl-   dba dibenzylideneacetone-   DCM dichloromethane-   DME 1,2-dimethoxyethane-   DMF dimethylformamide-   dppf 1,1′-bis(diphenylphosphino)-ferrocene-   DTT dithiothreitol-   ESMS electrospray mass spectrometry-   Ether ethyl ether-   EtOAc ethyl acetate-   Glu glutamic acid-   HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid-   HPLC high performance liquid chromatography-   LC-MS liquid chromatography-mass spectrometry-   Mc methyl-   MeOH methanol-   NMP N-methylpyrrolidone-   o-tol ortho-toluoyl-   Ph phenyl-   tBu tertiary butyl-   Tf trifluorosulfonyl-   TFA trifluoacetic acid-   Ts toluenesulfonyl

In general, the compounds of this invention may be prepared by methodsdescribed herein or known to those skilled in the art for thepreparation of analogous compounds. The following non-limiting schemesand examples are presented to further exemplify the invention.

General Synthetic Procedures

As shown in Scheme 1, a compound of formula III, containing leavinggroup Z (such as, for example, a halogen, phosphonate, tosylate, ortriflate) is reacted with a palladium catalyst/ligand system (such as,for example, Pd(PPh₃)₄, Pd(PtBu₃)₄, Pd[P(Me)(tBu₃)]₄, PdCl₂(PPh₃)₂,PdCl₂(dppf)₂, Pd₂(dba)₃BINAP, or Pd₂(dba)₃P(o-tol)₃ (see Fu and Littke,Angew. Chem. Int. Ed. 41:4176-4211, 2002; Nicolaou et al., Angew. Chem.Int. Ed. 44:4442-4489, 2005; or Hassen et al., Chemical Reviews102(5):1359-1469, 2002) in the presence of a base and a compound offormula IV, where M is —B(OAlkyl)₂ or —B(OH)₂(Suzuki reaction); —Mg-Hal(Kumada reaction); —Zn-Hal (Negishi reaction); —Sn(Alkyl)₃ (Stillereaction); —Si(Alkyl)₃ (Hiyama reaction); —Cu-Hal; —ZrCp₂Cl; or —AlMe₂;and P is a nitrogen protection group, to produce a compound of formulaV, where X², X⁴, X⁵, X⁶, X⁷, and R^(F) can be defined as indicatedelsewhere herein.

The protecting group, P, which can be, for example, an acetate or a Bocgroup, is removed by the requisite deprotection conditions and theresulting compound of formula V-a is reacted with a compound of formulaVI, where R^(G) and R^(H) are as defined elsewhere herein, under acidicconditions to produce a compound of formula II-b. The acid used can be amineral acid, such as, for example, hydrochloric or sulfuric acid; anorganic acid, such as, for example, acetic acid or trifluoroacetic acid;or a Lewis acid, such as, for example, boron trifluoride. Typically, thereaction mixture is heated, optionally under microwave radiation, toaffect the cyclization. If desired, the reaction mixture can be furtherheated, optionally under microwave irradiation, in the presence ofatmospheric oxygen or another oxidant to produce a compound in whichR^(F), R^(G), and the carbon and nitrogen atoms between them form acarbon-nitrogen double bond.

An alternate procedure useful for the preparation of a compound offormula II-b, where R^(G) is hydrogen (e.g., a compound of formulaII-d), or a compound of formula II-e, is shown in Scheme 2. The couplingof a compound of formula IV-a to a compound of formula III is performedas described above for the coupling of a compound of formula IV to acompound of formula III. The resulting compound of formula V-b issubjected to dehydration conditions to produce a compound of formulaII-c, where X², X⁴, X⁵, X⁶, X⁷, R^(F), and R^(H) can be defined asindicated elsewhere herein. Suitable reagents for this reaction include,for example, phosphorus oxychloride, thionyl chloride, phosphoroustribromide, phosphorous pentoxide, or any other suitable reagent foreffecting a Bischler-Napieralski-like reaction (see, for example,Schmutz et al., Helv. Chem. Acta 50:245, 1967 or Whaley andGovindachari, Org. React. 6:74, 1951). Typically, the reaction mixtureis heated to affect the cyclization. The compound of formula II-c canthen be reduced to produce a compound of formula II-d. Suitable reducingagents include hydride reducing agents, such as, for example, sodiumborohydride. Chiral borohydride reagents can also be used to influencethe chirality of the carbon bearing R^(H). Alternatively, when R^(F) ishydrogen, the reduction step can be omitted, thereby producing acompound of formula II-e.

When the compound of formula VI in Scheme 1 is an alpha-keto ester andit is reacted with a compound of formula V-a, the result is a compoundof V-c, where R^(G) is —C(O)OR(R is defined as indicated elsewhereherein). The 7-membered ring of a compound of formula V-c can be openedup by reduction, such as, for example, by hydrogenation, to give acompound of formula VII. Hydrolysis of the ester to the carboxylic acidof formula VIII and ring closure via condensation of the carboxylic acidwith the amine yields a compound of formula IX. Such a ring closure canbe performed using conventional condensation reagents known to a personskilled in the art, including, for example,1-benzotriazol-1-yloxy-bis(pyrrolidino)uronium hexafluorophosphate(BBC), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU),O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uroniumhexafluorophosphate (HAPyU),O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), 1,3-diisopropylcarbodiimide (DIC),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, (EDCI)O-(7-azabenzotriazol-1-yl)-tris(dimethylamino)phosphoniumhexafluorophosphate (AOP),1-benzotriazolyoxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), 7-azobenzotriazolyoxytris(pyrrolidino)phosphoniumhexafluorophosphate (PyABOP), and1-benzotriazolyoxytris(pyrrolidino)phosphonium hexafluorophosphate(PyBOP). When R^(F) is hydrogen, compounds of formula IX can be furtherelaborated by forming an imino triflate (by treatment with triflicanhydride and base) and using this intermediate in a catalyzedmetallation reaction, such as described above in Scheme 1, to producecompounds of formula I-a in which W is —NHC(═X)—, where X is [hydrogen,R].

Isomers of compounds of formula IX, where the amide bond has the reverseorientation, can be prepared as shown in Scheme 4. Metallation of1H-pyrrolo[2,3-b]pyridine followed by reaction with an appropriatelysubstituted imine, forms a compound of formula X, where R^(F) is asuitable amine protecting group, such as, for example, 4-methoxybenzylor trifluoromethylsulfonyl. Optionally, R^(F) is as defined for acompound of formula I-a and the amine is subsequently protected withprotecting group PG¹. A compound of formula X is reacted withmeta-chloroperbenzoic acid (mCPBA), or another suitable oxidant, to forman N-oxide intermediate. Subsequent reaction of this intermediate withtetramethylammonium bromide and methylsulfonyl anhydride forms acompound of formula XI, which is then treated with a phenylboronic acidanalog that contains an alpha carboxylic acid, which is protected with asuitable carboxylic acid protecting group PG², to produce a compound offormula XII. Methods for the preparation of aryl and alkenyl boronicacid analogs and their use in subsequent coupling reactions has beendescribed in U.S. Pat. Nos. 6,939,985 and 6,559,310, and in U.S. PatentApplication No. 20040133028. Deprotection of both carboxylic acid andamine protecting groups, followed by amide bond formation, such as, forexample, described above in Scheme 3, forms a compound of formula XIII.When R^(F) is hydrogen, compounds of formula IX can be furtherelaborated by forming an imino triflate and using this intermediate in acatalyzed metallation reaction, such as described above in Scheme 1, toproduce compounds of formula I-a in which W is —C(═X)NH—, where X is[hydrogen, R].

Alternatively, as shown in Scheme 5, a compound of formula XIV can bereacted with a compound of formula XV in a palladium catalyzedmetallation reaction to produce a compound of formula XVI. Subsequentreaction of this intermediate with an aldehyde, such as, for example,R^(H)—CHO, under acidic conditions produces a compound of formula XIII.Compounds 126, 127, and 129 were prepared in such a manner.

Example 1 Synthesis of Compound 5

As shown in Scheme 6,4-bromo-1H-pyrrolo[2,3-b]pyridine (1.01 g),2-acetamidophenylboronic acid (1.63 g), Pd(PPh₃)₄ (0.345 mg), and 1MNa₂CO₃ (8 mL) were mixed in DME (20 mL) and heated at 95° C. overnight.The reaction was cooled and water (60 mL) added. Extraction withdichloromethane (3×) and concentration of the combined organic extractsgave N-(2-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)acetamide (compound1001), which was treated with concentrated hydrochloric acid (20 mL) andtoluene (1 mL) and heated at 128° C. for 30 min. Evaporation of thevolatiles gave a residue, to which saturated sodium bicarbonate wasadded. The resulting mixture was extracted with dichloromethane (3×).Concentration of the organics and purification of the residue via silicagel chromatography (50 to 80% EtOAc/hexane) gave2-(1H-pyrrolo[2,3-b]pyridin-4-yl)benzenamine (compound 1002, 1.07 g). Tocompound 1002 (14 mg) in methanol (1 mL) was added 4N HCl-dioxane (0.05mL) and benzaldehyde (16 mg). The reaction mixture was capped and heatedat 90° C. for 1 h. About 75% of the methanol was removed by evaporation,followed by the addition of ethyl ether (5 mL). The resulting solid wasfiltered and washed with ether (2×) to yield compound 5 as thehydrochloride salt (22.5 mg).

Compounds 1, 6-22, 24-43, 45-46, 60, 64-80, 86-89, 91, 104-108, 110-112,114, and 119-124, and 128 (see Table 1 for compound structures) wereprepared from compound 1002 by varying the aldehyde and using aprocedure similar to that for the synthesis of compound 5.

Compound 23 was obtained by treating compound 8 with refluxing 6M HClfor 1 hour.

Compound 90 was obtained by hydrogenation of compound 89 over 10% Pd/C.

In the preparation of compound 43, compound 44 was also obtained by HPLCpurification.

Compound 93 was obtained by treating compound 83 with SnCl₂.2H₂O inrefluxing ethanol for 4 hours.

Compound 58 was obtained via reaction of compound 1002 with2-ethoxytetrahydropyran in methanol/4M HCl-dioxane at 90° C. When thesame components were reacted in a microwave at 120° C. for 20 minutes,compound 59 was obtained. Substituting 2-ethoxytetrahydrofuran for2-ethoxytetrahydropyran in an analogous microwave procedure producedcompound 60.

Compound 63 was obtained by heating compound 46 in methanol for 3 daysat 90° C.

Example 2 Synthesis of Compound 102

As shown in Scheme 7, compound 1002 (66 mg), 4-nitrophenylglyoxylic acid(135 mg), 4M HCl-dioxane (0.4 mL), and methanol (4 mL) were mixedtogether and heated at 90° C. overnight. After cooling, addition ofether, and filtration, compound 98 was obtained as a solid (106 mg). Tocompound 98 (64 mg) in 3 mL of methanol was added SnCl₂.2H₂O (0.3 g).After heating at 80° C. for 1 hour, followed by cooling, the reactionmixture was filtered through Celite™ and concentrated to give compound102 after purification via silica gel chromatography.

Example 3 Synthesis of Compound 125

As shown in Scheme 8, compound 1002 (58 mg), 4-hydroxyphenylglyoxylicacid (69 mg), 4M HCl-dioxane (0.4 mL), and methanol (4 mL) were mixedtogether and heated at 90° C. overnight. After cooling, the addition ofether and filtration, compound 103 (0.11 g) was obtained as a yellowsolid. To compound 103 (24.4 mg), methanol (2 mL), and 2 drops ofconcentrated hydrochloric acid was added 10% Pd/C (8 mg). The resultingsuspension was stirred under a hydrogen balloon for 24 hours. Filtrationthrough Celite™ and evaporation under vacuum gave compound 1003 (25 mg).Compound 1003 (20 mg) was refluxed in 6 M hydrochloric acid for 6 hours.Evaporation under vacuum gave the intermediate carboxylic acid, whichwas dissolved in DMF (2 mL), followed by the addition of2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) (40 mg) and diisopropylethylamine (DIEA, 0.02mL). The resulting mixture was stirred at 40° C. overnight, followed bythe addition of water (20 mL) and TFA (0.1 mL). The crude product wasextracted with ethyl acetate (3×), dried over Na₂SO₄, concentrated invacuo, and purified by HPLC to obtain compound 125.

Example 4 Synthesis of Compound 3

As shown in Scheme 9, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.02 g,mmol), 2-acetamidophenylboronic acid (1.80 g), Pd(PPh₃)₄ (0.4 g), and 1MNa₂CO₃ (8 mL) were mixed in DME (20 mL) and heated at 95° C. overnight.The reaction was cooled and the solvents were removed in vacuo, followedby the addition of water (60 mL). Extraction with dichloromethane (3×)and concentration of the combined organic extracts gave, after silicagel chromatography,N-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)acetamide (compound 1004),which was subsequently treated with concentrated hydrochloric acid (20mL) and toluene (1 mL). The resulting mixture was heated for 30 min at128° C. The volatiles were removed in vacuo to give a solid, to whichsaturated sodium bicarbonate was added. Extraction with 5% MeOH/DCM (3×)and concentration under reduced pressure gave a residue, to which etherwas added. The resulting solid was filtered and washed with ether (2×)to give 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzenamine (compound 1005)as a yellow solid (1.17 g).

A mixture of compound 1005 (10 mg), benzaldehyde (20 mg), 4M HCl-dioxane(0.1 mL), and methanol (1 mL) were heated at 95° C., and the progress ofthe reaction was monitored by LC-MS. When the reaction was judgedcomplete, the reaction mixture was concentrated and ether was added.Compound 3 was filtered off and obtained as an HCl salt.

Compounds 2, 4, 49-50, 55-56, 81-85, 115-116, and 118 (see Table 1 forcompound structures) were prepared from compound 1005 by varying thealdehyde and using a procedure similar to that for the synthesis ofcompound 3. Compound 117 was isolated as a side product during thepurification of compound 116

Compound 92 was prepared by reacting compound 1005 (10.5 mg),4-hydroxybenzaldehyde (15 mg), and TFA (1 mL) at 140° C. for 20 minutesunder microwave radiation. The crude product was isolated by removal ofthe solvents in vacuo, followed by HPLC purification.

Example 5 Synthesis of Compound 48

As shown in Scheme 10, 4-bromo-1H-pyrrolo[2,3-b]pyridine (0.11 g, mmol),2,2-dimethyl-N-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-propionamide(0.304 g), Pd(PPh₃)₄ (0.04 mg), and 1M Na₂CO₃ (0.8 mL) were mixed in DME(3 mL) and heated at 95° C. overnight. The reaction mixture was cooledand water (20 mL) was added. Extraction with dichloromethane (3×) andconcentration of the combined organic extracts gave, after silica gelchromatography (1:1 ethyl acetate/hexanes), compound 1006, which wassubsequently treated with refluxing concentrated hydrochloric acid (10mL) for two days. The liquid was removed under vacuum to give a solid,to which saturated sodium bicarbonate was added. Extraction withdichloromethane (3×) and concentration under a reduced pressure gave aresidue, to which ether was added. Filtration gave compound 1007 (48mg).

A mixture of compound 1007 (10 mg), 3-fluorobenzaldehyde (20 mg), 4MHCl-dioxane (0.1 mL), and methanol (1 mL) was heated at 160° C. undermicrowave radiation for 40 minutes. The reaction mixture wasconcentrated in vacuo and ether was added. Compound 48 was filtered offand subsequently purified by HPLC.

Compounds 47, 95, and 97 (see Table 1 for compound structures) wereprepared from compound 758545 by varying the aldehyde and using aprocedure similar to that for the synthesis of compound 48. Compound 96was isolated as a by-product during the purification of compound 97.

Example 6 Synthesis of Compound 52

As shown in Scheme 11, mCPBA (4.75 g) was added to a solution of5-chloro-1H-pyrrolo[2,3-b]pyridine (3.00 g) in ethyl acetate (20 mL) at0° C. The reaction mixture was stirred at room temperature for 12 hoursand the solvents removed in vacuo to leave a residue, to which aqueous30% potassium carbonate was added. Extraction with 10% MeOH/DCM (5×) andevaporation gave the crude N-oxide, which was used directly in the nextreaction.

To the N-oxide in DMF at 0° C. (10 mL) was added tetramethyl ammoniumbromide (1.00 g) and methylsulfonyl anhydride (1.5 g). The reactionmixture was stirred at 0° C. for 30 minutes and brought to roomtemperature over 2 hours. Water (40 mL) was added, followed byextraction with dichloromethane (3×) and concentration of the combinedorganics in vacuo. Silica gel chromatography (0 to 40% EtOAc/DCM) gave4-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine, which was contaminated withthe corresponding 3-bromo and 3,4-dibromo compounds.

To the mixture of the bromides (0.128 g) in 1,4-dioxane (4 mL) was added2-acetamidophenylboronic acid (0.20 g), PdCl₂dppf₂ (0.04 mg) andpotassium phosphate (0.47 g). The reaction mixture was heated at 90° C.overnight. The reaction mixture was cooled and water (20 mL) was added.Extraction with dichloromethane (3×) and concentration of the combinedorganic extracts gave a mixture of 3- and 4-regional isomers, which wereseparated by silica gel chromatography (0 to 100% EtOAc/hexane) toproduce the 4-isomer (compound 1008, 26 mg) as a pure compound. Compound1008 was refluxed in concentrated hydrochloric acid for 50 min.Concentration of the reaction mixture in vacuo gave compound 1009.

Compound 1009 (6 mg) was mixed with the 2,6-difluorobenzaldehyde (20 mg)in methanol and 4N HCl-dioxane (0.1 mL). The resulting solution washeated at 95° C. and the progress of the reaction was monitored byLC-MS. When the reaction was judged to be complete, the mixture wasconcentrated in vacuo and ether was added. Compound 52 was isolated asthe HCl salt.

Compounds 53 and 54 (see Table 1 for compound structures) were preparedfrom compound 1009 by varying the aldehyde and using a procedure similarto that for the synthesis of compound 52.

Example 7 Synthesis of Compound 51

As shown in Scheme 12, a solution of compound 1010 (19 mg) in benzeneand POCl₃ (0.2 mL) was heated at 90° C. for 2 hours. Additional POCl₃(0.2 mL) was added and heating was continued for and additional 2 hours.Evaporation, addition of saturated sodium bicarbonate, extraction withdichloromethane (3×), and silica gel chromatography (EtOAc) gavecompound 51 (7.3 mg).

Analytical Characterization

Spectral data for selected compounds of the invention are presented inTable 2. 1H-NMR spectra were taken at 500 MHz unless indicatedotherwise.

TABLE 2 Cmpd. ESMS ¹H-NMR No. (M + 1) NMR peaks given as δ values 1342.90 (methanol-d₄) 8.40 (d, 1H), 8.16 (d, 1H), 7.89 (d, 1H), 7.59 (s,1H), 7.54 (dd, 1H), 7.41 (d, 1H), 7.36 (dd, 1H), 7.31-7.27 (m, 5H), 4.99(dd, 1H), 4.49 (d, 1H), 4.42 (d, 1H), 3.73 (dd, 1H), 3.51 (dd, 1H) 2343.20 (methanol-d₄) 8.90 (s, 1H), 8.18 (d, 1H), 7.88 (d, 1H), 7.57 (dd,1H), 7.35 (d, 1H), 7.12-6.98 (m, 5H), 6.25 (dd, 1H), 4.49 (m, 2H), 4.28(d, 1H), 3.80 (dd, 1H), 3.70 (dd, 1H) 3 299.20 (methanol-d₄) 8.93 (s,1H), 8.32 (d, 1H), 7.94 (d, 1H), 7.61 (dd, 1H), 7.46 (d, 1H), 7.41-7.31(m, 5H), 7.15 (m, 3H) 4 291.20 (methanol-d₄) 9.11 (s, 1H), 8.43 (d, 1H),7.98 (d, 1H), 7.69 (dd, 1H), 7.59 (d, 1H), 7.18 (d, 1H), 7.07 (dd, 1H) 5297.90 (methanol-d₄) 8.59 (d, 1H), 8.26 (d, 1H), 8.09 (d, 1H), 7.54 (dd,1H), 7.37-7.33 (m, 8H), 6.18 (s, 1H) 6 278.20 (methanol-d₄) 8.33 (d,1H), 8.10 (d, 1H), 7.88 (d, 1H), 7.48 (s, 1H), 7.46 (dd, 1H), 7.25 (d,1H), 7.18 (dd, 1H), 3.64 (s, 1H), 0.89 (s, 9H) 7 315.90 (methanol-d₄)8.46 (d, 1H), 8.14 (d, 1H), 7.97 (d, 1H), 7.40 (dd, 1H), 7.33-7.16 (m,5H), 7.00 (dd, 1H), 6.90 (dd, 1H), 6.18 (s, 1H), 3.66 (s, 1H) 8 294.20(methanol-d₄) 8.35 (d, 1H), 8.09 (d, 1H), 7.90 (d, 1H), 7.61 (s, 1H),7.45 (dd, 1H), 7.21 (dd, 1H), 7.19 (dd, 1H), 5.37 (s, 1H), 4.04 (q, 2H),1.08 (t, 3H) 9 328.20 (methanol-d₄) 8.60 (d, 1H), 8.22 (d, 1H), 8.06 (d,1H), 7.55 (dd, 1H), 7.53-7.31 (m, 4H), 7.12 (d, 1H), 6.74 (m, 2H), 6.48(s, 1H), 4.03 (s, 3H) 10 304.30 (methanol-d₄) 8.36-7.30 (m, 7H), 4.39(m, 1H), 2.08-0.97 (m, 11H) 11 316.20 (methanol-d₄) 8.49-6.99 (m, 11 H),5.93 (s, 1H), 3.66 (s, 1H) 12 316.20 (methanol-d₄) 8.56-7.07 (m, 11 H),6.13 (s, 1H), 3.66 (s, 1H) 13 222.20 (methanol-d₄) 8.49 (d, 1H), 8.28(d, 1H), 7.97 (d, 1H), 7.67 (s, 1H), 7.65 (d, 1H), 7.58 (dd, 1H), 7.53(d, 1H), 4.73 (s, 2H) 14 250.10 (methanol-d₄) 8.82 (d, 1H), 8.30 (d,1H), 8.02 (d, 1H), 7.78 (s, 1H), 7.70 (d, 1H), 7.65 (dd, 1H), 7.64 (d,1H), 4.91 (dd, 1H), 1.90 (m, 1H), 1.60 (m, 1H), 1.08 (t, 3H) 15 278.20(methanol-d₄) 8.52 (d, 1H), 8.31 (d, 1H), 8.03 (d, 1H), 7.74 (s, 1H),7.70 (d, 1H), 7.64 (dd, 1H), 7.60 (d, 1H), 5.08 (dd, 1H), 1.76 (m, 1H),1.62 (m, 1H), 1.37 (m, 1H), 1.03 (d, 3H), 0.92 (d, 3H) 16 264.20(methanol-d₄) 8.37-7.26 (m, 6H), 4.34 (dd, 1H), 1.79 (m, 1H), 1.10 (d,3H), 0.86 (d, 3H) 17 332.00 (methanol-d₄) 8.41 (d, 1H), 8.09 (d, 1H),7.93 (d, 1H), 7.47 (d, 1H), 7.33 (dd, 1H), 7.24 (dd, 1H), 7.19 (s, 1H),7.17-7.05 (m, 3H), 6.91 (d, 1H), 6.12 (s, 1H) 18 334.00 (methanol-d₄)8.49 (d, 1H), 8.21 (d, 1H), 8.02 (d, 1H), 7.51 (dd, 1H), 7.49 (dd, 1H),7.42 (dd, 1H), 7.31 (d, 1H), 7.26 (s, 1H), 7.07 (d, 1H), 7.05 (d, 1H),6.21 (s, 1H) 19 366.10 (methanol-d₄) 8.49 (d, 1H), 8.24 (d, 1H), 8.03(d, 1H), 7.88 (d, 1H), 7.74 (dd, 1H), 7.65 (s, 1H), 7.64 (d, 1H), 7.52(dd, 1H), 7.39 (dd, 1H), 7.30 (d, 1H), 6.87 (s, 1H), 5.86 (s, 1H) 20314.20 (methanol-d₄) 8.62-6.61 (m, 10 H), 6.49 (s, 1H) 21 375.90(methanol-d₄) 8.42-6.95 (m, 10 H), 6.07 (s, 1H) 22 342.20 (methanol-d₄)8.45-6.74 (m, 10 H), 5.94 (s, 2 H), 5.75 (s, 1H) 23 266.20 (methanol-d₄)8.41-7.21 (m, 7H), 5.41 (s, 1 H) 24 312.20 (methanol-d₄) 8.32 (d, 1H),8.14 (d, 1H), 7.84 (d, 1H), 7.40 (dd, 1H), 7.29-7.21 (m, 5H), 7.08 (s,1H), 7.07 (d, 1H), 6.93 (d, 1H), 4.86 (dd, 1H), 3.05 (dd, 1H), 2.97 (dd,1H) 25 334.20 (methanol-d₄) 8.41 (d, 1H), 8.07 (d, 1H), 7.92 (d, 1H),7.34 (dd, 1H), 7.31 (s, 1H), 7.15 (m, 2H), 7.07 (d, 1H), 6.90 (m, 1H),6.61 (dd, 1H), 6.08 (s, 1H) 26 334.20 (methanol-d₄) 8.40 (dd, 1H), 8.08(d, 1H), 7.91 (d, 1H), 7.67-7.54 (m, 2H), 7.35 (dd, 1H), 7.26 (s, 1H),7.17 (dd, 1H), 7.08 (d, 1H), 7.00 (dd, 1H), 6.01 (s, 1H) 27 334.20(methanol-d₄) 8.40 (dd, 1H), 8.09 (d, 1H), 7.91 (dd, 1H), 7.34 (dd, 1H),7.31 (s, 1H), 7.16 (m, 2H), 7.07 (d, 1H), 6.98 (m, 1H), 6.51 (m, 1H),6.03 (s, 1H) 28 334.20 (methanol-d₄) 8.39 (dd, 1H), 8.09 (d, 1H), 7.91(dd, 1H), 7.37 (dd, 1H), 7.27 (s, 1H), 7.16 (dd, 1H), 7.08 (d, 1H), 6.82(m, 3H), 5.75 (s, 1H) 29 352.10 (methanol-d₄) 8.40 (d, 1H), 8.07 (d,1H), 7.91 (d, 1H), 7.36 (dd, 1H), 7.33 (s, 1H), 7.16 (dd, 1H), 7.07 (d,1H), 6.86 (m, 1H), 6.61 (m, 1H), 6.04 (s, 1H) 30 352.10 (methanol-d₄)8.39 (d, 1H), 8.12 (d, 1H), 7.93 (d, 1H), 7.38 (dd, 1H), 7.30 (m, 1H),7.26 (s, 1H), 7.22 (dd, 1H), 7.10 (d, 1H), 6.97 (m, 1H), 6.06 (s, 1H) 31352.10 (methanol-d₄) 8.41 (d, 1H), 8.09 (d, 1H), 7.91 (d, 1H), 7.36 (dd,1H), 7.33 (s, 1H), 7.21 (ddd, 1H), 7.17 (dd, 1H), 7.07 (d, 1H), 6.71(ddd, 1H), 6.00 (s, 1H) 32 350.10 (methanol-d₄) 8.41 (d, 1H), 8.08 (d,1H), 7.92 (d, 1H), 7.34 (dd, 1H), 7.30 (dd, 1H), 7.22 (s, 1H), 7.16 (dd,1H), 7.07 (s, 1H), 6.91 (dd, 1H), 6.86 (ddd, 1H), 6.08 (s, 1H) 33 350.10(methanol-d₄) 8.39 (d, 1H), 8.13 (d, 1H), 7.92 (d, 1H), 7.41 (m, 3H),7.24 (dd, 1H), 7.17 (dd, 1H), 7.08 (dd, 1H), 7.05 (s, 1H), 7.18 (s, 1H)34 384.10 (methanol-d₄) 8.40 (d, 1H), 8.16 (d, 1H), 7.93 (d, 1H),7.74-7.50 (m, 4 H), 7.27 (dd, 1H), 7.23 (d, 1H), 6.70 (s, 1H), 5.83 (s,1H) 35 343.20 (methanol-d₄) 8.43 (d, 1H), 8.10 (d, 1H), 7.95 (d, 1H),7.46 (dd, 1H), 7.31 (dd, 1H), 7.29 (s, 1H), 7.16 (dd, 1H), 7.06 (d, 1H),6.96 (d, 1H), 6.16 (s, 1H) 36 316.80 (methanol-d₄) 8.39 (d, 1H), 8.03(d, 1H), 8.01 (d, 1H), 7.81 (d, 1H), 7.33 (s, 1H), 7.28 (dd, 1H), 7.24(dd, 1H), 7.11 (dd, 1H), 7.03 (d, 1H), 7.02 (dd, 1H), 6.01 (s, 1H) 37298.90 (methanol-d₄) 8.59 (d, 1H), 8.42 (d, 1H), 8.06 (dd, 1H), 7.88 (d,1H), 7.56 (dd, 1H), 7.50 (d, 1H), 7.38 (s, 1H), 7.33 (dd, 1H), 7.16 (dd,1H), 7.07 (d, 1H), 6.06 (s, 1H) 38 299.20 (methanol-d₄) 8.60 (d, 1H),8.54 (s, 1H), 8.40 (d, 1H), 8.19 (d, 1H), 8.07 (d, 1H), 7.83 (d, 1H),7.77 (dd, 1H), 7.31 (dd, 2H), 7.13 (dd, 1H), 7.02 (d, 1H), 5.96 (s, 1H)39 350.10 (methanol-d₄) 8.39 (d, 1H), 8.08 (d, 1H), 7.90 (d, 1H), 7.37(m, 2H), 7.21 (s, 1H), 7.16 (dd, 1H), 7.10 (d, 1H), 7.07 (d, 1H), 7.04(d, 1H), 5.72 (s, 1H) 40 332.20 (methanol-d₄) 8.39 (d, 1H), 8.10 (d,1H), 7.90 (d, 1H), 7.64-7.55 (m, 2H), 7.35 (m, 2 H), 7.27 (s, 2 H), 7.17(dd, 1H), 7.07 (d, 1H), 5.70 (s, 1H) 41 366.00 (methanol-d₄) 8.42 (d,1H), 8.07 (d, 1H), 7.92 (d, 1H), 7.40 (d, 1H), 7.32 (dd, 1H), 7.29 (s,1H), 7.14 (dd, 1H), 7.03 (d, 1H), 7.02 (dd, 1H), 6.77 (d, 1H). 6.17 (s,1H) 42 366.00 (methanol-d₄) 8.38 (d, 1H), 8.15 (d, 1H), 7.92 (d, 1H),7.66-7.50 (m, 2 H), 7.44 (d, 1H), 7.42 (dd, 1H), 7.25 (d, 1H), 7.22 (d,1H), 6.84 (s, 1H), 6.36 (s, 1H) 43 299.20 (methanol-d₄) 8.61 (d, 2H),8.40 (d, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.70 (d, 2H), 7.44 (s, 1H),7.28 (dd, 1H), 7.10 (d, 1H), 6.98 (d, 1H), 6.05 (s, 1H) 44 297.20(methanol-d₄) 8.88 (d, 2H), 8.29 (d, 1H), 8.11 (m, 1H), 7.86 (m, 3H),7.58 (d, 1H), 7.46 (dd, 2H), 7.37 (dd, 1H) 45 346.20 (methanol-d₄) 8.48(d, 2H), 8.18 (d, 1H), 7.98 (d, 1H), 7.46 (dd, 1H), 7.37 (dd, 1H), 7.26(s, 1H), 7.23 (dd, 1H), 7.05 (m, 3 H), 5.89 (s, 1H), 3.84 (s, 3H) 46348.20 (methanol-d₄) 8.45 (d, 2H), 8.14 (d, 1H), 7.96 (d, 1H), 7.43 (dd,1H), 7.31 (dd, 1H), 7.21 (s, 1H), 7.20 (d, 1H), 6.92 (d, 1H), 6.81 (d,1H), 6.57 (dd, 1H), 6.12 (s, 1H); Lot 3: (d4-MeOH) 6.24 (1H, s), 6.60(1H, dd), 6.85 (1H, d), 6.95 (1H, d), 7.28 (1H, d), 7.31 (1H, s), 7.41(1H, dd), 7.50 (1H, dd), 8.02 (1H, d), 8.20 (1H, dd), 8.52 (1H, d) 47335.20 (methanol-d₄) 8.92 (d, 1H), 8.43 (d, 1H), 8.29 (d, 1H), 7.88 (d,1H), 7.46-7.32 (m, 2H), 7.20 (s, 1H), 7.03 (dd, 2H), 6.38 (s, 1H) 48317.20 (methanol-d₄) 8.83 (d, 1H), 8.42 (d, 1H), 8.29 (d, 1H), 7.82 (d,1H), 7.35-7.26 (m, 2 H), 7.24 (s, 1H), 7.09 (d, 1 H), 7.02 (m, 2 H),5.96 (s, 1H) 49 335.20 (CDCl₃) 10.41 (s, 1H), 9.00 (s, 1H), 8.75 (d,1H), 7.34 (dd, 1H), 7.31 (dd, 1H), 7.26 (s, 1H), 7.19 (dd, 1H), 6.97(dd, 2H), 6.88 (d, 1H), 6.80 (s, 1H), 6.04 (s, 1H) 50 317.20(methanol-d₄) 9.06 (s, 1H), 8.32 (d, 1H), 7.95 (d, 1H), 7.63 (dd, 1H),7.46 (d, 1H), 7.38 (dd, 1H), 7.27 (s, 1H), 7.20-7.07 (m, 3 H), 7.03 (d,1H) 51 234.20 (methanol-d₄, for free base) 8.13 (d, 1H), 7.99 (d, 1H),7.98 (s, 1H), 7.42-7.28 (m, 4 H), 2.47 (s, 3H) 52 368.10 (methanol-d₄)8.55 (s, 1H), 8.54 (d, 1 H), 7.74 (dd, 1 H), 7.68-7.56 (mn, 3 H), 7.20(dd, 2 H), 7.14 (s, 1 H), 6.28 (s, 1 H) 53 382.00 (methanol-d₄) 8.50 (s,1H), 8.41 (d, 1 H), 7.52 (dd, 1 H), 7.46 (dd, 1H), 7.31-7.22 (m, 2 H),6.95 (dd, 1 H), 6.81-6.56 (m, 2H), 6.31 (s, 1 H) 54 386.10 (methanol-d₄)8.56 (s, 1H), 8.52 (d, 1 H), 7.70 (dd, 1 H), 7.63 (dd, 1H), 7.54 (m, 2H), 7.26 (s, 1H), 7.18 (m, 1H), 6.0 (s, 1 H) 55 349.20 (methanol-d₄)8.94 (s, 1H), 8.11 (d, 1H), 7.48 (dd, 1H), 7.27 (s, 1H), 7.21 (dd, 1H),7.19 (d, 1H), 6.90 (d, 1H), 6.83 (d, 1H), 6.58 (dd, 1H), 6.04 (s, 1H) 56353.10 (CDCl₃) 9.60 (s, 1H), 9.01 (s, 1H), 8.75 (dd, 1H), 7.37-6.81 (m,6H), 6.05 (s, 1H), 4.49 (s, 1H) 57 349.20 (methanol-d₄) 8.45 (d, 1H),8.32 (d, 1H), 8.12 (d, 1H), 7.54 (d, 1H), 7.09 (dd, 1H), 6.96 (s, 1H),6.86 (d, 1H), 6.77 (d, 1H), 6.51 (d, 1H), 6.02 (s, 1H) 58 292.30(methanol-d₄) 8.70 (s, 1H), 8.29 (d, 1H), 8.12 (d, 1H), 7.58 (d, 1H),7.48 (m, 2H), 7.41 (d, 1H), 3.68 (t, 2H), 3.03 (t, 2H), 1.97 (m, 2H),1.77 (m, 2H) 59 294.30 (methanol-d₄) 8.33 (d, 1H), 8.14 (d, 1H), 7.80(d, 1H), 7.48 (dd, 1H), 7.47 (s, 1H), 7.29 (d, 1H), 4.62 (dd, 1H), 3.52(t, 2 H), 1.76- 1.48 (m, 6 H) 60 280.30 (methanol-d₄) 8.33 (d, 1H), 8.14(d, 1H), 7.79 (d, 1H), 7.49 (dd, 1H), 7.48 (s, 1H), 7.30 (d, 1H), 4.65(dd, 1H), 3.56 (t, 2 H), 1.82- 1.64 (m, 4 H) 61 348.20 62 348.20 63346.20 (methanol-d₄) 8.31 (d, 1H), 8.12 (d, 1H), 7.82 (s, 1H), 7.60 (d,1H), 7.56 (d, 1H), 7.48 (m, 2H), 7.32 (m, 1H), 7.11 (s, 1H), 6.99 (d,1H) 64 360.20 (methanol-d₄) 8.39 (d, 1H), 8.14 (d, 1H), 7.83 (d, 1H),7.41 (dd, 1H), 7.35-6.41 (m, 5 H), 5.61 (s, 1H), 3.66 (s, 3H) 65 314.20(methanol-d₄) 8.59 (d, 1H), 8.28 (d, 1H), 8.09 (d, 1H), 7.62 (dd, 1H),7.58 (dd, 1H), 7.38 (s, 1H), 7.37 (d, 1H), 7.17 (d, 2H), 6.78 (d, 2H),6.13, (s, 1H) 66 330.20 (methanol-d₄) 8.42 (d, 1H), 8.16 (d, 1H), 7.86(d, 1H), 7.44 (dd, 1H), 7.36 (dd, 1H), 7.23 (s, 1H), 7.08 (s, 1H),6.77-6.69 (m, 3H), 5.65 (s, 1H) 67 382.00 (methanol-d₄) 8.39 (d, 1H),8.11 (d, 1H), 7.90 (d, 1H), 7.39 (dd, 1H), 7.22-7.10 (m, 3 H), 7.17 (s,2H), 5.61 (s, 1H) 68 362.20 (methanol-d₄) 8.43 (d, 1H), 8.16 (d, 1H),7.93 (d, 1H), 7.44 (dd, 1H), 7.31 (dd, 1H), 7.20 (d, 1H), 7.20 (s, 1H),6.77 (s, 1H), 6.60 (d, 1H), 5.73 (s, 1H), 3.77 (s, 3H) 69 330.20(methanol-d₄) 8.61 (d, 1H), 8.25 (d, 1H), 8.07 (d, 1H), 7.64 (dd, 1H),7.58 (dd, 1H), 7.53 (d, 1H), 7.52 (dd, 1H), 6.80 (d, 1H), 6.50 (dd, 1H),6.48 (s, 1H), 6.21 (br s, 1H) 70 378.10 (methanol-d₄) 8.41 (d, 1H), 8.09(d, 1H), 7.90 (d, 1H), 7.36 (dd, 1H), 7.22 (s, 1H), 7.21 (d, 1H), 7.10(d, 1H), 6.66 (d, 1H), 6.34 (d, 1H), 6.10 (s, 1H), 3.83 (s, 3H) 71359.10 (methanol-d₄) 8.44 (d, 1H), 8.10 (d, 1H), 8.04 (d, 1H), 7.96 (d,1H), 7.40 (s, 1H), 7.32 (dd, 1H), 7.18 (dd, 1H), 6.92 (d, 1H), 6.72 (dd,1H), 6.46 (s, 1H), 6.28 (d, 1H) 72 330.20 (methanol-d₄) 8.61 (d, 1H),8.25 (d, 1H), 8.06 (d, 1H), 7.62 (dd, 1H), 7.60 (dd, 1H), 7.56 (dd, 1H),7.50 (d, 1H), 6.76 (d, 1H), 6.62 (d, 1H), 6.43 (s, 1H), 6.10 (s, 1H) 73344.20 (methanol-d₄) 8.57 (d, 1H), 8.27 (d, 1H), 8.06 (d, 1H), 7.58 (m,2H), 7.38 (d, 1H), 7.36 (s, 1H), 6.97 (s, 1H), 6.77 (m, 2H), 6.07 (s,1H), 3.77 (s, 3H) 74 348.20 (methanol-d₄) 8.50 (d, 1H), 8.20 (d, 1H),7.99 (d, 1H), 7.50 (dd, 1H), 7.42 (dd, 1H), 7.26 (m, 3H), 7.09 (d, 1H),6.88 (d, 1H), 5.88 (s, 1H) 75 440.10 (methanol-d₄) 8.51 (d, 1H), 8.22(d, 1H), 8.01 (d, 1H), 7.65 (s, 1H), 7.51 (dd, 1H), 7.45 (dd, 1H), 7.28(d, 1H), 7.26 (s, 1H), 7.15 (d, 1H), 6.80 (d, 1H), 5.88 (s, 1H) 76422.10 (methanol-d₄) 8.40 (d, 1H), 8.13 (d, 1H), 7.90 (d, 1H), 7.66-7.07(m, 4 H), 7.04 (s, 1H), 6.65 (s, 1H), 5.92 (s, 1H), 3.56 (s, 3H) 77392.00 (methanol-d₄) 8.38 (d, 1H), 8.10 (d, 1H), 7.87 (d, 1H), 7.66-7.10(m, 6 H), 6.85 (d, 1H), 5.60 (s, 1H) 78 469.90 (methanol-d₄) 8.38 (d,1H), 8.10 (d, 1H), 7.87 (d, 1H), 7.66-7.10 (m, 5 H), 6.85 (d, 1H), 5.60(s, 1H) 79 342.20 (methanol-d₄) 8.41 (d, 1H), 8.17 (d, 1H), 7.85 (d,1H), 7.66-6.91 (m, H), 5.61 (s, 1H), 2.18 (s, 6H) 80 332.30(methanol-d₄) 8.40 (d, 1H), 8.10 (d, 1H), 7.82 (d, 1H), 7.53-7.09 (m, 5H), 6.53 (s, 1H) 81 349.20 (methanol-d₄) 8.92 (s, 1H), 8.09 (d, 1H),7.50 (dd, 1H), 7.25 (s, 2H), 7.21 (d, 1H), 7.06 (d, 1H), 6.86 (d, 1H),5.62 (s, 1H) 82 393.00 (methanol-d₄) 8.80 (s, 1H), 8.53 (d, 1H), 7.44(s, 1H), 7.29 (dd, 1H), 7.10 (dd, 1H), 7.08 (d, 1H), 7.04 (d, 1H), 6.83(d, 1H), 6.82 (s, 1H), 5.43 (s, 1H) 83 329.20 (methanol-d₄) 8.88 (s,1H), 8.19 (d, 1H), 7.45 (dd, 1H), 7.19 (m, 2H), 7.08 (s, 1H), 7.03 (s,1H), 6.98 (d, 1H), 6.72 (d, 1H), 5.49 (s, 1H), 2.10 (s, 3H) 84 345.20(methanol-d₄) 8.92 (s, 1H), 8.11 (d, 1H), 7.50 (dd, 1H), 7.24 (d, 1H),7.20 (s, 2H), 6.96 (s, 1H), 6.75 (d, 1H), 6.70 (d, 1H), 5.60 (s, 1H),3.79 (s, 3H) 85 375.20 (methanol-d₄) 8.92 (s, 1H), 8.13 (d, 1H), 7.51(dd, 1H), 7.25 (d, 1H), 7.23 (s, 1H), 7.21 (d, 1H),. 6.63 (s, 2H), 5.60(s, 1H), 3.75 (s, 6H) 86 342.70 (methanol-d₄) 8.43 (d, 1H), 8.12 (d,2H), 8.10 (d, 1H), 7.94 (d, 1H), 7.46 (d, 2H), 7.35 (dd, 1H), 7.29 (s,1H), 7.17 (dd, 1H), 7.09 (d, 1H), 5.93 (s, 1H) 87 356.10 (methanol-d₄)8.43 (d, 1H), 8.12 (d, 1H), 7.94 (dd, 1H), 7.93 (d, 2H), 7.38 (dd, 1H),7.36 (d, 2H), 7.22 (s, 1H), 7.21 (d, 1H), 7.12 (d, 1H), 5.88 (s, 1H),3.87 (s, 3H) 88 342.20 (D₂O) 8.46 (d, 1H), 8.08 (d, 1H), 7.92 (d, 1H),7.89 (d, 2H), 7.46 (dd, 1H), 7.38 (dd, 1H), 7.33 (s, 1H), 7.27 (d, 2H),7.15 (s, 1H), 5.95 (s, 1H) 89 438.90 (methanol-d₄) 8.44-7.25 (m, 12 H),5.07 (s, 2H), 4.60 and 4.51 (2 br s, 1H), 4.14 and 4.03 (2d, 2H),2.75-1.28 (m, 7H) 90 305.30 (methanol-d₄) 8.31 (br s, 1H), 8.10 (d, 1H),7.75 (br s, 1H), 7.40 (m, 3H), 7.17 (d, 1H), 7.12 (dd, 1H), 4.31 (br s,1H), 3.38 (dd, 2H), 2.71 (m, 2H), 2.21 (d, 1H), 1.72 (m, 2H), 1.58 (m,2H) 91 355.20 (CDCl₃) 8.73 (s, 1H), 8.39 (d, 1H), 8.01 (d, 1H), 7.80 (d,2H), 7.49 (d, 2H), 7.46 (d, 1H), 7.24 (dd, 1H), 7.15 (dd, 1H), 6.87 (d,1H), 6.47 (s, 1H), 6.12 (br s, 1H), 5.47 (s, 1H), 3.05 (d, 3H) 92 313.20(methanol-d₄) 8.90 (d, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 7.82 (d, 2H),7.63 (dd, 1H), 7.57 (m, 2H), 7.10 (d, 2 H) 93 313.20 (methanol-d₄) 8.25(d, 1H), 7.95 (d, 1H), 7.48 (d, 1H), 7.21 (dd, 1H), 7.11 (d, 2H), 7.10(dd, 1H), 7.03 (d, 1H), 6.70 (d, 2H), 6.65 (s, 1H), 5.27 (s, 1H) 94310.80 (methanol-d₄) 8.31 (d, 1H), 8.12 (s, 1H), 8.07 (d, 1H), 7.62 (d,1H), 7.61 (d, 2H), 7.50-7.42 (m, 2H), 7.39 (dd, 1H), 6.85 (d, 2H) 95362.80 (methanol-d₄) 8.65 (d, J = 8.0 Hz, 1 H), 8.49 (d, J = 6.8 Hz, 1H), 8.35 (d, J = 4.6 Hz, 1 H), 7.96 (d, J = 6.8 Hz, 2 H), 7.36 (s, 1 H),7.20-7.18 (m, 2 H), 7.05 (dd, J = 8.4, 2.0 Hz, 1 H), 6.83 (d, J = 8.4Hz, 1 H), 5.80 (s, 1 H), 4.41 (s, 3 H) 96 328.80 (methanol-d₄) 8.60 (d,1H), 8.46 (d, 1H), 8.33 (d, 1H), 7.94 (d, 2 H), 7.20 (s, 1H), 7.16 (dd,1H), 7.14 (d, 2H), 6.74 (d, 2H), 5.71 (s, 1H), 4.39 (s, 3 H) 97 314.80(methanol-d₄) 8.94 (dd, J = 8.0, 1.4 Hz, 1 H), 8.41 (d, J = 5.9 Hz, 1H), 8.28 (dd, J = 5.5, 1.6 Hz, 1 H), 7.81 (d, J = 6.0 Hz, 1 H), 7.33(dd, J = 8.0, 5.5 Hz, 1 H), 7.19 (d, J = Hz, 2 H), 7.04 (s, 1 H), 6.80(d, J = Hz, 2H), 5.80 (s, 1 H) 98 400.80 (methanol-d₄) 8.42 (d, J = 6.6Hz, 1 H), 8.13 (d, J = 8.9 Hz, 2 H), 8.00 (d, J = 8.1 Hz, 1 H), 7.90 (d,J = 6.6 Hz, 1 H), 7.47 (d, J = 8.9 Hz, 2 H), 7.41-7.38 (m, 1 H), 7.34(s, 1 H), 7.28 (d, J = 8.1 Hz, 1 H), 7.14 (t, J = 7.1 Hz, 1 H), 3.80 (s,3 H) 99 371.50 (CDCl₃) 8.82 (s, 1 H), 8.38 (d, J = 5.1 Hz, 1 H), 8.01(d, J = 8.0 Hz, 1 H), 7.51-7.39 (m, 4 H), 7.20 (s, 1 H), 7.16-7.13 (m, 1H), 6.89 (d, J = 7.9 Hz, 1 H), 6.73 (s, 1 H), 6.68 (s, 1 H), 6.49 (s, 1H), 5.50 (s, 1 H), 5.36 (s, 1 H), 3.71 (s, 3 H) 100 429.50 (methanol-d₄)8.48 (d, 1 H), 8.07 (d, 1 H), 7.96 (d, 1 H), 7.43 (d, 2 H), 7.34 (dd, 1H), 7.26 (s, 1H), 7.23 (d, 2 H), 7.18 (dd, 1 H), 7.13 (d, 1 H), 5.50 (s,1 H), 4.10 (s, 3 H), 3.73 (s, 3 H) 101 487.50 (methanol-d₄) 8.50-7.04(m, 11 H), 5.68 (s, 1 H), 4.14 (s, 3 H), 4.08 (s, 3 H), 3.67 (s, 3 H)102 370.90 (CDCl₃) 9.58 (s, 1 H), 8.29 (d, J = 5.3 Hz, 1 H), 7.78 (d, J= 7.8 Hz, 1 H), 7.33 (d, J = 5.3 Hz, 1 H), 7.12 (t, J = 7.2 Hz, 1 H),7.02 (s, 1 H), 6.98 (d, J = 8.5 Hz, 2 H), 6.84 (d, J = 7.9 Hz, 1 H),6.46 (d, J = 8.5 Hz, 2 H), 5.29 (s, 1 H), 3.70 (d, J = 4.0 Hz, H), 3.66(s, 3 H), 3.55 (br s, 2H) 103 372.50 (methanol-d₄) 8.37 (d, J = 6.6 Hz,H), 8.02 (d, J = 8.1 Hz, H), 7.88 (d, J = 6.7 Hz, H), 7.40 (dd, J = 7.6Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.16 (dd, J = 7.9 Hz, 1H), 7.14 (s,1H), 7.06 (dd, J = 1.9, 6.8 Hz, 2 H), 6.71 (d, J = 6.8 Hz, 2 H), 3.70(s, 3 H) 104 382.40 (methanol-d₄) 8.39 (d, J = 6.4 Hz, 1 H), 8.12-8.11(m, 1 H), 7.87 (d, J = 6.5 Hz, 1 H), 7.45 (d, J = 2.0 Hz, 1 H), 7.39(dd, J = 6.6 and 1.2 Hz, , 1 H), 7.31 (dd, J = 2.1, 8.5 Hz, 1 H), 7.22(ddd, J = 8, 8 and 0.9 Hz, 1 H), 7.13 (dd, J = 0.9, 8.1 Hz, 1 H), 7.05(s, 1 H), 6.90 (d, J = 8.5 Hz, 1 H), 5.65 (s, 1 H) 105 332.40(methanol-d₄) 8.58 (d, J = 6.4 Hz, 1 H), 8.26 (dd, J = 3.4, 6.0 Hz, 1H), 8.08 (d, J = 6.5 Hz, 1 H), 7.55 (m, 2 H), 7.42 (s, 1 H), 7.35 (dd, J= 3.4, 5.9 Hz, 1 H), 7.04 (dd, J = 1.9, 11.7 Hz, 1 H), 6.97 (d, J = 8.4Hz, 1 H), 6.89 (dd, J = 7.9 and 7.9 Hz, H), 6.12 (s, 1 H) 106 350.40(methanol-d₄) 8.41 (d, J = 6.5 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 7.92(d, J = 6.5 Hz, 1 H), 7.41 (dd, J = 8 and 8 Hz, 1 H), 7.23 (d, J = 6.0Hz, 2 H), 7.14 (d, J = 8.1 Hz, 1 H), 6.81 (d, J = 8.8 Hz, 2 H), 5.70 (s,1 H) 107 332.40 (methanol-d₄) 8.60 (d, 1 H), 8.27 (d, 1 H), 8.10 (d, 1H), 7.64-7.57 (m, 2 H), 7.49 (s, 1 H), 7.42-7.39 (m, 1 H), 6.81 (dd, 1H), 6.64 (dd, 1 H), 6.48 (dd, 1 H), 6.36 (s, 1 H) 108 426.50(methanol-d₄) 8.61 (d, J = 6.2 Hz, 1 H), 8.30 (d, J = 7.9 Hz, 1 H), 8.08(d, J = 6.2 Hz, 1 H), 7.63 (d, J = 7.7 Hz, 1 H), 7.56 (d, J = 7.6 Hz, 1H), 7.42 (s, 1 H), 7.29 (d, J = 7.7 Hz, 1 H), 7.12 (s, 1 H), 6.17 (s, 1H), 1.33 (s, 18 H) 109 220.30 (methanol-d₄) 8.39 (s, 1 H), 8.26 (d, J =5.4 Hz, 1 H), 8.22 (s, 1 H), 8.10-8.08 (m, 1 H), 7.52 (d, J = 5.5 Hz, 1H), 7.47-7.44 (m, 2H), 7.18-7.16 (m, 1 H) 110 358.40 (methanol-d₄) 8.40(d, H), 8.11 (d, 1 H), 7.87 (d, 1, H), 7.80 (s, 1H), 7.43-7.36 (m, 2 H),7.22 (dd, 1 H), 7.14 (d, 1 H), 7.07 (s, 1 H), 6.90 (d, 1 H), 5.66 (s, 1H) 111 372.50 (methanol-d₄) 8.39 (d, J = 6.4 Hz, 1 H), 8.11 (d, J = 8.1Hz, 1 H), 7.88 (d, J = 6.5 Hz, 1 H), 7.80 (d, J = 2.3 Hz, 1 H), 7.44(dd, J = 2.3, 8.6 Hz, 1 H), 7.38 (dd, J = 9 and 9 Hz, 1 H), 7.22 (dd, J= 9.1 and 9.1 Hz, H), 7.13 (d, J = 8.0 Hz, 1 H), 7.06 (s, 1 H), 6.93 (d,J = 8.6 Hz, 1 H), 5.65 (s, 1 H), 3.89 (s, 3 H) 112 378.40 (methanol-d₄)8.39 (d, 1H), 8.11 (d, 1H), 7.87 (d, 1 H), 7.41-7.36 (m, 1 H), 7.24 (dd,1 H), 7.14 (d, 1 H), 7.13 (s, 1H), 6.86 (d, 1 H), 6.79 (d, 1 H), 5.62(s, 1 H), 3.77 (s, 3 H) 113 396.40 (methanol-d₄) 8.31 (d, J = 5.4 Hz, 1H), 8.10 (dd, J = 4.8 Hz, 1 H), 7.98 (s, 1 H), 7.80 (d, J = 0.9 Hz, 1 H)7.70 (dd, J = 2.3, 8.5 Hz, 1 H), 7.61 (d, J = 5.5 Hz, 1 H), 7.48-7.36(m, 3 H), 7.25 (d, J = 8.5 Hz, 1 H) 114 398.40 (methanol-d₄) 8.39 (d, J= 5.9 Hz, 1 H), 8.10 (d, J = 7.2 Hz, 1 H), 7.87 (d, J = 6.4 Hz, 1 H),7.37-7.07 (m, 6 H), 6.90 (d, J = 8.4 Hz, 1 H), 5.67 (s, 1 H) 115 351.30(methanol-d₄) 8.90 (s, 1H), 8.14 (d, 1H), 7.47 (dd, 1H), 7.30 (s, 1H),7.18 (dd, 1H), 7.16 (d, 1H), 6.81 (d, 2H), 5.65 (s, 1H) 116 333.30(methanol-d₄) 8.91 (s, 1H), 8.10 (d, J = 8.3 Hz, 1 H), 7.48 (t, J = 7.6Hz, 1 H), 7.24 (s, 1 H), 7.20-7.18 (m, 2 H), 7.00 (d, J = 12.0 Hz, 1 H),6.91 (d, J = 8.3 Hz, 1 H), 6.86 (t, J = 8.5 Hz, 1 H), 5.62 (s, 1 H) 117347.30 (methanol-d₄) 9.03 (s, 1 H), 8.72 (d, 1H), 7.41 (dd, 1H), 7.19(d, 1H), 7.08 (d, 1H), 7.07 (dd, 1H), 6.99 (d, 1H), 6.92 (d, 1H), 6.85(dd, 1H), 5.63 (s, 1H), 4.30 (s, 3 H) 118 333.30 (methanol-d₄) 8.94 (s,1 H), 8.07 (dd, 1 H), 7.49 (ddd, 1H), 7.33 (s, 1H), 7.21 (dd, 1H), 7.20(d, 1H), 6.78 (dd, 1H), 6.57 (dd, 1H), 6.45 (dd, 1H), 5.94 (s, 1H) 119364.30 120 365.30 (DMSO-d₆) 12.00 (s, H), 11.96 (s, H), 9.20 (s, H),8.36 (d, J = 5.7 Hz, H), 8.18 (s, H), 8.00 (d, J = 7.8 Hz, H), 7.72 (d,J = 8.4 Hz, H), 7.65 (s, H), 7.61 (d, J = 5.6 Hz, 2H), 7.53 (s, H), 7.34(d, J = 8.5 Hz, 2H), 7.22-7.17 (m, H), 7.09 (d, J = 8.0 Hz, H), 5.75 (s,H). 121 376.30 (DMSO-d₆) 11.82 (s, H), 10.14 (s, H), 8.33 (d, J = 5.5Hz, H), 8.16 (s, H), 7.97 (d, J = 8.1 Hz, H), 7.79 (d, J = 8.3 Hz, 2H),7.55 (d, J = 5.7 Hz, H), 7.45-7.41 (m, 2H), 7.19-7.16 (m, H), 7.04 (d, J= 8.0 Hz, H), 7.00-6.97 (m, H), 5.74 (s, H), 3.14 (s, 3H). 122 315.20123 391.30 (DMSO-d₆) 11.89 (s, H), 9.66 (s, H), 8.35 (d, J = 5.6 Hz, H),8.00 (d, J = 7.9 Hz, 2H), 7.59 (d, J = 5.6 Hz, 2H), 7.23-7.21 (m, H),7.17 (d, J = 8.3 Hz, H), 7.12 (s, H), 7.09 (d, J = 8.4 Hz, H), 7.03 (s,H), 5.61 (s, H), 3.17 (s, 3H). 124 332.20 (DMSO-d₆) 11.92 (s, H), 11.87(s, H), 8.32 (d, J = 5.7 Hz, H), 7.98 (d, J = 8.0 Hz, H), 7.56 (d, J =5.6 Hz, H), 7.36 (s, H), 7.25-7.22 (m, H), 7.09 (d, J = 7.9 Hz, H), 7.02(t, J = 7.5 Hz, H), 6.43 (s, H), 5.81 (s, H), 2.23 (s, 3H), 1.91 (s, 3H)125 342.40 (methanol-d₄) 8.41 (d, J = 5.8 Hz, 1 H), 7.76-7.72 (m, 1 H),7.67- 7.65 (m, 2 H), 7.44 (d, = 8.5 Hz, 2 H), 7.42-7.38 (m, 2 H), 7.12(d, J = 1.0 Hz, 1 H), 6.81 (d, J = 8.5 Hz, 2 H), 5.25 (s, 1 H) 126356.10 127 360.10 128 342.40 (methanol-d₄) 8.53 (d, J = 6.1 Hz, 1 H),8.21 (d, J = 7.8 Hz, 1 H), 8.03 (d, J = 6.3 Hz, 1 H), 7.67-7.27 (m, 8H), 6.04 (s, 1 H) 129 370.10 (methanol-d₄) 8.39 (d, H), 7.77-7.64 (m,3H), 7.53 (d, H), 7.37 (d, H), 7.28 (m, 2H), 6.96 (d, H), 6.76 (s, H),5.95 (s, H), 4.88 (s, H), 4.72 (s, H), 3.87 (s, 3H), 2.21 (s, 3H). 130418.40 (methanol-d₄) 8.25 (d, 1 H), 7.83 (d, 1 H), 7.41 (d, 1 H),7.37-6.85 (m, 7 H), 4.27-4.15 (m, 2 H), 3.74 (s, 3 H), 1.15 (t, 3 H) 131438.10 (DMSO-d₆) 11.90 (s, H), 8.35 (d, J = 5.6 Hz, H), 7.98 (d, J = 7.9Hz, H), 7.71-7.57 (m, H), 7.51-7.46 (m, 2H), 7.39-7.32 (m, 2H), 7.22-7.15 (m, 2H), 7.10-7.07 (m, 2H), 7.03-7.00 (m, H), 6.85 (d, J = 6.6 Hz,2H), 6.78 (d, J = 7.6 Hz, H), 5.66 (s, H). 132 418.10 (DMSO-d₆) 11.92(s, H), 8.37 (d, J = 5.6 Hz, H), 8.00 (d, J = 7.8 Hz, H), 7.61 (d, J =5.5 Hz, H), 7.39 (d, J = 7.3 Hz, 2H), 7.30-6.95 (m, 8H), 6.73 (s, 2H),6.04 (s, H), 2.30 (s, 3H), 2.12 (s, 2H). 133 328.10 (DMSO-d₆) 11.99 (s,H), 8.39 (m, H), 8.08 (d, H), 7.68 (d, H), 7.36- 7.09 (m, 3H), 6.92-6.73(m, 2H), 6.65 (s, H), 6.50 (s, H), 2.35 (s, 3H). 134 382.10 135 328.10(DMSO-d₆) 11.96 (s, H), 8.37 (d, J = 5.6 Hz, H), 8.02 (d, J = 7.9 Hz,H), 7.64 (dd, J = 5.7, 16.8 Hz, H), 7.26-7.22 (m, 2H), 6.82 (d, J = 8.4Hz, 2H), 5.66 (s, H), 3.69 (s, 3H). 136 366.10 (DMSO-d₆) 11.91 (s, H),8.35 (d, J = 5.6 Hz, H), 7.98 (d, J = 8.1 Hz, H), 7.61-7.57 (m, 3H),7.38 (d, J = 8.0 Hz, 2H), 7.22-7.14 (m, 2H), 6.99 (t, J = 7.5 Hz, 2H),6.86 (s, br, H), 5.75 (s, H). 137 312.10 (DMSO-d₆) 12.04 (s, H), 8.38(d, J = 5.7 Hz, H), 8.03 (t, J = 8.0 Hz, H), 7.64 (d, J = 5.8 Hz, H),7.33-6.99 (9H), 5.68 (s, H), 2.23 (s, 3H). 138 330.40 139 359.40 140328.40 141 340.40 142 358.40 143 415.40 144 356.40 145 356.40 146 356.40147 390.40 148 358.10 149 378.10 150 360.30 (methanol-d₄) 8.39 (d, 1H),7.71 (dd, 1H), 7.64 (d, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 7.41 (dd, 1H),7.33 (d, 1H), 7.13 (d, 1H), 7.06 (s, 1H), 6.91 (dd, 1H), 5.27 (s, 1H)151 401.40 (methanol-d₄) 8.93 (s, 1 H), 8.02 (d, 1 H), 7.55 (dd, 1H),7.43 (d, 1H), 7.40 (s, 1H), 7.22 (dd, 1H), 7.18 (d, 2H), 6.86 (d, 2H),4.23 (q, 2H), 3.65 (s, 3 H), 1.14 (t, 3H) 152 403.90 153 375.90 154328.00 155 261.00 156 294.00 157 413.10 158 342.90 (methanol-d₄) 8.92(s, 1H); 7.88 (d, 1H); 7.80 (dd, 1H); 7.72 (dd, 1H); 7.50 (d, 1H); 7.42(d, 2H); 7.20 (s, 1H); 6.82 (d, 2H); 5.15 (s, 1H) 159 357.00(methanol-d₄) 8.90 (s, 1H); 7.88 (d, 1H); 7.82 (dd, 1H); 7.75 (dd, 1H);7.62 (d, 1H); 7.42 (d, 2H); 7.15 (s, 1H); 7.78 (d, 2H); 5.22 (s, 1H);3.15 (s, 3H) 160 361.30 (DMSO-d₆) 12.35 ppm (bs, 0.5H), 12.1 (bs, 0.5H),8.9 (s, 0.5H), 8.85 (s, 0.5H), 7.9 (dd, 0.5H), 7.8 (s, 0.5H), 7.5 to7.65 (m, 3H), 7.3 (dd, 0.5H), 7.1 to 7.2 (m, 2H), 6.85 to 6.95 (m,1.5H), 6.7 (dd, 0.5H), 6.5 (t, 0.5H), 6.25 to 6.4 (m, 1H), 5.1 (s,0.5H), 5.05 (s, 0.5H). 161 341.30 (DMSO-d₆) 12.3 ppm (bs, 0.63H), 12.1(bs, 0.37H), 9.55 (s, 0.37H), 9.35 (s, 0.63H), 8.9 (s, 1H), 7.9 (dd,0.37H), 7.75 (d, 0.63H), 7.6 (m, 1H), 7.5 (t, 2H), 7.3 (dd, 0.37H), 7.0to 7.2 (m, 2H), 6.9 (s, 0.37H), 6.5 to 6.7 (m, 2.25H), 5.15 (s, 1H),2.35 (s, 1.13H), 2.0 (s, 1.9H). 162 465.30 (DMSO-d₆, 300 MHz) 12.75 (s,1H), 8.46 (d, J = 11 Hz, 1H), 8.06 (d, J = 12.5 Hz, 1H), 7.82 (d, J = 11Hz, 1H), 7.41 (m, 6H), 7.30 (m, 2H), 7.19 (m, 2H), 7.11 (m, 2H), 6.93(d, J = 14 Hz, 1H), 5.89 (s, 1H), 3.31 (br s, 3H).

Example 8 JAK-3 Inhibition Assay

Compounds were screened for their ability to inhibit JAK using the assayshown below. Reactions were carried out in a kinase buffer containing100 mM HEPES (pH 7.4), 1 mM DTT, 10 mM MgCl₂, 25 mM NaCl, and 0.01% BSA.

Substrate concentrations in the assay were 5 μM ATP (200 μCi/μmole ATP)and 1 μM poly(Glu)₄Tyr. Reactions were carried out at 25° C. and 1 nMJAK-3.

To each well of a 96 well polycarbonate plate was added 1.5 μl, of acandidate JAK-3 inhibitor along with 50 μL of kinase buffer containing 2μM poly(Glu)₄Tyr and 10 μM ATP. This was then mixed and 50 μL, of kinasebuffer containing 2 nM JAK-3 enzyme was added to start the reaction.After 20 minutes at room temperature (25° C.), the reaction was stoppedwith 50 μl, of 20% trichloroacetic acid (TCA) that also contained 0.4 mMATP. The entire contents of each well were then transferred to a 96 wellglass fiber filter plate using a TomTek Cell Harvester. After washing,60 μL of scintillation fluid was added and ³³P incorporation detected ona Perkin Elmer TopCount. After removing the mean background values forall of the data points, the data were fit using Prism software to obtaina K, value (app).

Example 9 JAK-2 Inhibition Assay

The JAK-2 assays were performed as described above in Example 8 exceptthat JAK-2 enzyme was used, the final poly(Glu)₄Tyr concentration was 15μM, and final ATP concentration was 12 μM. Selected results arepresented in Table 1.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference. Although the foregoing invention has been described in somedetail by way of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to those of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

1-20. (canceled)
 21. A method of inhibiting JAK kinase activity in an invitro biological sample comprising contacting said biological samplewith a compound having the formula (I-a) or a pharmaceuticallyacceptable salt thereof:

wherein W is —N(R^(F))—, —C(X)N(R^(F))— or —N(R^(F))C(X)—; X is O, S,[hydrogen, hydrogen] or [hydrogen, R]; X² is N or C—R^(X2) whereinR^(X2) is hydrogen, halogen, —CN, —NO₂, —OR^(X2B)—OC(O)R^(X2B)—,—OC(O)OR^(X2B), —OC(O)NR^(X2A)R^(X2B), —OC(S)R^(X2B), —SR^(X2B),—SC(O)R^(X2B), —SC(S)R^(X2B), —C(O)OR^(X2B), —C(O)NR^(X2A)R^(X2B),—C(S)NR^(X2A)R^(X2B), —NR^(X2A)R^(X2B), —S(O)R^(X2B), —S(O)₂R^(X2B),—S(O)₂NR^(X2A)R^(X2B), C₁₋₄ haloaliphatic, optionally substituted C₃₋₈cycloaliphatic, C₁₋₆ aliphatic; X⁴ is N or C—R^(B4), X⁵ is N orC—R^(B5), X⁶ is N or C—R^(B6), and X⁷ is N or C—R^(B7), where optionallyup to two of X⁴, X⁵, X⁶, and X⁷ are N and each of R^(B4), R^(B5),R^(B6), and R^(B7) is, independently, hydrogen, halogen, —CN, —NO₂, —OR,—OC(O)R, —OC(O)OR, —OC(O)NRR′, —OC(S)R, —SR, —SC(O)R, —SC(S)R, —C(O)OR,—C(O)NRR′, —C(S)NRR′, —NRR′, —S(O)R, —S(O)₂R, —S(O)₂NRR′, optionallysubstituted C¹⁻⁴ haloaliphatic, C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic,C₆₋₁₀ aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-memberedbicyclic heterocyclyl, or 5- to 8-membered monocyclic heteroaryl, 8- to12-membered bicyclic heteroaryl; each of R^(F) and R^(G) is,independently, hydrogen, optionally substituted C₁₋₆ aliphatic, C₁₋₄haloaliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl, 3- to 8-memberedmonocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl,or when W is N(R^(F)), R^(F) and R^(G) and the intervening atomstogether optionally form a N═C bond; R^(H) is hydrogen, optionallysubstituted C₁₋₆ aliphatic, C₁₋₄ haloaliphatic, C₃₋₈ cycloaliphatic,C₆₋₁₀ aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-memberedbicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to12-membered bicyclic heteroaryl; R^(X2A) is hydrogen, optionallysubstituted C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl, 3- to8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclicheterocyclyl, 5- to 8-membered monocyclic heteroaryl, 8- to 12-memberedbicyclic heteroaryl, —C(O)R, —C(O)NRR′, —C(O)OR, —S(O)R, —S(O)₂R, or—S(O)₂NRR′; each of R, R′, and R^(X2B) is, independently, hydrogen,optionally substituted C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl,3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclicheterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to12-membered bicyclic heteroaryl; each of said heterocyclyl andheteroaryl rings contains one to four heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen; the optional substituents on one ormore carbon atoms of each of said aryl and heteroaryl groups are:halogen; —R^(∘); —OR^(∘); —SR^(∘); 1,2-methylenedioxy;1,2-ethylenedioxy; phenyl optionally substituted with R^(∘); —O(Ph)optionally substituted with R^(∘); —(CH₂)₁₋₂(Ph) optionally substitutedwith R^(∘); —CH═CH(Ph) optionally substituted with R^(∘); —NO₂; —CN;—N(R^(∘))₂; —NR^(∘)C(O)R^(∘); —NR^(∘)C(S)R^(∘); —NR^(∘)C(O)N(R^(∘))₂;—NR^(∘)C(S)N(R^(∘))₂; —NR^(∘)C(O)OR^(∘); —NR^(∘)NR^(∘)C(O)R^(∘);—NR^(∘)NR^(∘)C(O)N(R^(∘))₂; —NR^(∘)NR^(∘)C(O)OR^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(O)OR^(∘); —C(O)R^(∘); —C(S)R^(∘); —C(O)N(R^(∘))₂;—C(S)N(R^(∘))₂; —B(OR^(∘))₂, —OC(O)N(R^(∘))₂; —OC(O)R^(∘);—C(O)N(OR^(∘))R^(∘); —C(═NOR^(∘))R^(∘); —S(O)₂R^(∘); —S(O)₂OR^(∘);—S(O)₂N(R^(∘))₂; —S(O)R^(∘); —NR^(∘)S(O)₂N(R^(∘))₂; —NR^(∘)S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(═NH)—N(R^(∘))₂; or —(CH₂)₀₋₂NHC(O)R^(∘); -L-R^(∘);-L-N(R^(∘))₂; -L-SR^(∘); -L-OR^(∘); -L-(C₃₋₁₀ cycloaliphatic), -L-(C₆₋₁₀aryl), -L-(5-10 membered heteroaryl), -L-(5-10 membered heterocyclyl),oxo, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, -L-NO₂, -L-CN, -L-OH, -L-CF₃; ortwo substituents, on the same carbon or on different carbons, togetherwith the carbon or intervening carbons to which they are bound, form a5-7 membered saturated, unsaturated, or partially saturated ring,wherein L is a C₁₋₆ alkylene group in which up to three methylene unitsare replaced by —NH—, —NR^(∘)—, —O—, —S—, —C(O)O—, —OC(O)—, —C(O)C(O)—,—C(O)—, —C(O)NH—, —C(O)NR^(∘)—, —C(═N—CN)—, —NHC(O)—, —NR^(∘)C(O)—,—NHC(O)O—, —NR^(∘)C(O)O—, —S(O)₂NH—, —S(O)₂NR^(∘)—, —NHS(O)₂—,—NR^(∘)S(O)₂—, —NHC(O)NH—, —NR^(∘)C(O)NH—, —NHC(O)NR^(∘)—,—NR^(∘)C(O)NR^(∘), —OC(O)NH—, —OC(O)NR^(∘)—, —NHS(O)₂NH—,—NR^(∘)S(O)₂NH—, —NHS(O)₂NR^(∘)—, —NR^(∘)S(O)₂NR^(∘)—, —S(O)—, or—S(O)₂—, and wherein each occurrence of R^(∘) is independently selectedfrom hydrogen, optionally substituted C₁₋₆ aliphatic, an unsubstituted5- to 6-membered heteroaryl or heterocyclic ring, phenyl, or —CH₂(Ph),or, two independent occurrences of R^(∘), on the same substituent ordifferent substituents, taken together with the atom(s) to which eachR^(∘) group is bound, form a 5-8-membered heterocyclyl, aryl, orheteroaryl ring or a 3- to 8-membered cycloalkyl ring, wherein saidheteroaryl or heterocyclyl ring has 1 to 3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein optional substituentson the aliphatic group of R^(∘) are selected from —NH₂, —NH(C₁₋₄aliphatic), —N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄aliphatic), —NO₂, —CN, —C(O)OH, C(O)O(C₁₋₄ aliphatic), O(haloC₁₋₄aliphatic), or haloC₁₋₄ aliphatic wherein each of the C₁₋₄ aliphaticgroups of R^(∘) is unsubstituted; and the optional substituents on oneor more carbon atoms of each of said aliphatic, haloaliphatic, cycloaliphatic, and heterocyclyl groups are as defined for said aryl andheteroaryl groups and additionally comprise: ═O, ═S, ═NNHR*, ═NN(R*)₂,═NNHC(O)R*, ═NNHC(O)O(alkyl), ═NNHS(O)₂(alkyl), or ═NR*, wherein each R*is independently selected from hydrogen or an optionally substitutedC₁₋₆ aliphatic, and where optional substituents on said aliphatic groupof R* are selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂,halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic), —NO₂, —CN, —C(O)OH,—C(O)O(C₁₋₄ aliphatic), —O(halo-C₁₋₄ aliphatic), and halo(C₁₋₄aliphatic), wherein each of the foregoing C₁₋₄ aliphatic groups of R* isunsubstituted.
 22. The method according to claim 21, wherein said JAKkinase is JAK-3.
 23. The method according to claim 21, wherein said JAKkinase is JAK-2.
 24. A method of treating or lessening the severity of adisease, condition, or disorder in a patient, comprising administering atherapeutically effective amount of a compound having the formula (I-a)or a pharmaceutically acceptable salt thereof:

wherein W is —N(R^(F))—, —C(X)N(R^(F))— or —N(R^(F))C(X)—; X is O, S,[hydrogen, hydrogen] or [hydrogen, R]; X² is N or C—R^(X2), whereinR^(X2) is hydrogen, halogen, —CN, —NO₂, —OR^(X2B), —OC(O)R^(X2B),—OC(O)OR^(X2B), —OC(O)NR^(X2A)R^(X2B), —OC(S)R^(X2B), —SR^(X2B),—SC(O)R^(X2B), —SC(S)R^(X2B), —C(O)OR^(X2B), —C(O)NR^(X2A)R^(X2B),C(S)NR^(X2A)R^(X2B), —NR^(X2A)R^(X2B), —S(O)R^(X2B), S(O)₂R^(X2B),—S(O)₂NR^(X2A)R^(X2B), C₁₋₄ haloaliphatic, optionally substituted C₃₋₈cycloaliphatic, C₁₋₆ aliphatic; X⁴ is N or C—R^(B4), X⁵ is N orC—R^(B5), X⁶ is N or C—R^(B6), and X⁷ is N or C—R^(B7), where optionallyup to two of X⁴, X⁵, X⁶, and X⁷ are N and each of R^(B4), R^(B5),R^(B6), and R^(B7) is, independently, hydrogen, halogen, —CN, —NO₂, —OR,—OC(O)R, —OC(O)OR, —OC(O)NRR′, —OC(S)R, —SR, —SC(O)R, —SC(S)R, —C(O)OR,—C(O)NRR′, —C(S)NRR′, —NRR′, —S(O)R, —S(O)₂R, —S(O)₂NRR′, optionallysubstituted C₁₋₄ haloaliphatic, C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic,C₆₋₁₀ aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-memberedbicyclic heterocyclyl, or 5- to 8-membered monocyclic heteroaryl, 8- to12-membered bicyclic heteroaryl; each of R^(F) and R^(G) is,independently, hydrogen, optionally substituted C₁₋₆ aliphatic, C₁₋₄haloaliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl, 3- to 8-memberedmonocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl,or when W is N(R^(F)), R^(F) and R^(G) and the intervening atomstogether optionally form a N═C bond; R^(H) is hydrogen, optionallysubstituted C₁₋₆ aliphatic, C₁₋₄ haloaliphatic, C₃₋₈ cycloaliphatic,C₆₋₁₀ aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-memberedbicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to12-membered bicyclic heteroaryl; R^(X2A) is hydrogen, optionallysubstituted C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl, 3- to8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclicheterocyclyl, 5- to 8-membered monocyclic heteroaryl, 8- to 12-memberedbicyclic heteroaryl, —C(O)R, —C(O)NRR′, —C(O)OR, —S(O)R, —S(O)₂R, or—S(O)₂NRR′; each of R, R′, and R^(X2B) is, independently, hydrogen,optionally substituted C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl,3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclicheterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to12-membered bicyclic heteroaryl; each of said heterocyclyl andheteroaryl rings contains one to four heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen; the optional substituents on one ormore carbon atoms of each of said aryl and heteroaryl groups are:halogen; —R^(∘); —OR^(∘); —SR^(∘); 1,2-methylenedioxy;1,2-ethylenedioxy; phenyl optionally substituted with R^(∘); —O(Ph)optionally substituted with R^(∘); —(CH₂)₁₋₂(Ph) optionally substitutedwith R^(∘); —CH═CH(Ph) optionally substituted with R^(∘); —NO₂; —CN;—N(R^(∘))₂; —NR^(∘)C(O)R^(∘); —NR^(∘)C(S)R^(∘); —NR^(∘)C(O)N(R^(∘))₂;—NR^(∘)C(S)N(R^(∘))₂; —NR^(∘)C(O)OR^(∘); —NR^(∘)NR^(∘)C(O)R^(∘);—NR^(∘)NR^(∘)C(O)N(R^(∘))₂; —NR^(∘)NR^(∘)C(O)OR^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(O)OR^(∘); —C(O)R^(∘); —C(S)R^(∘); —C(O)N(R^(∘))₂;—C(S)N(R^(∘))₂; —B(OR^(∘))₂, —OC(O)N(R^(∘))₂; —OC(O)R^(∘);—C(O)N(OR^(∘))R^(∘); —C(═NOR^(∘))R^(∘); —S(O)₂R^(∘); —S(O)₂OR^(∘);—S(O)₂N(R^(∘))₂; —S(O)R^(∘); —NR^(∘)S(O)₂N(R^(∘))₂; —NR^(∘) S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(═NH)—N(R^(∘))₂; or —(CH₂)₀₋₂NHC(O)R^(∘); -L-R^(∘);-L-N(R^(∘))₂; -L-SR^(∘); -L-OR^(∘); -L-(C₃₋₁₀ cycloaliphatic), -L-(C₆₋₁₀aryl), -L-(5-10 membered heteroaryl), -L-(5-10 membered heterocyclyl),oxo, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, -L-NO₂, -L-CN, -L-OH, -L-CF₃; ortwo substituents, on the same carbon or on different carbons, togetherwith the carbon or intervening carbons to which they are bound, form a5-7 membered saturated, unsaturated, or partially saturated ring,wherein L is a C₁₋₆ alkylene group in which up to three methylene unitsare replaced by —NH—, —NR^(∘)—, —O—, —S—, —C(O)O—, —OC(O)—, —C(O)C(O)—,—C(O)—, —C(O)NH—, —C(O)NR^(∘)—, —C(═N—CN)—, —NHC(O)—, —NR^(∘)C(O)—,—NHC(O)O—, —NR^(∘)C(O)O—, —S(O)₂NH—, —S(O)₂NR^(∘)—, —NHS(O)₂—,—NR^(∘)S(O)₂—, —NHC(O)NH—, —NR^(∘)C(O)NH—, —NHC(O)NR^(∘)—,—NR^(∘)C(O)NR^(∘), —OC(O)NH—, —OC(O)NR^(∘)—, —NHS(O)₂NH—,—NR^(∘)S(O)₂NH—, —NHS(O)₂NR^(∘)—, —NR^(∘)S(O)₂NR^(∘)—, —S(O)—, or—S(O)₂—, and wherein each occurrence of R^(∘) is independently selectedfrom hydrogen, optionally substituted C₁₋₆ aliphatic, an unsubstituted5- to 6-membered heteroaryl or heterocyclic ring, phenyl, or —CH₂(Ph),or, two independent occurrences of R^(∘), on the same substituent ordifferent substituents, taken together with the atom(s) to which eachR^(∘) group is bound, form a 5-8-membered heterocyclyl, aryl, orheteroaryl ring or a 3- to 8-membered cycloalkyl ring, wherein saidheteroaryl or heterocyclyl ring has 1 to 3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein optional substituentson the aliphatic group of R^(∘) are selected from —NH₂, —NH(C₁₋₄aliphatic), —N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄aliphatic), —NO₂, —CN, —C(O)OH, C(O)O(C₁₋₄ aliphatic), O(haloC₁₋₄aliphatic), or haloC₁₋₄ aliphatic, wherein each of the C₁₋₄ aliphaticgroups of R^(∘) is unsubstituted; and the optional substituents on oneor more carbon atoms of each of said aliphatic, haloaliphatic, cycloaliphatic, and heterocyclyl groups are as defined for said aryl andheteroaryl groups and additionally comprise: ═O, ═S, ═NNHR*, ═NN(R*)₂,═NNHC(O)R*, ═NNHC(O)O(alkyl), ═NNHS(O)₂(alkyl), or ═NR*, wherein each R*is independently selected from hydrogen or an optionally substitutedC₁₋₆ aliphatic, and where optional substituents on said aliphatic groupof R* are selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂,halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic), —NO₂, —CN, —C(O)OH,—C(O)O(C₁₋₄ aliphatic), —O(halo-C₁₋₄ aliphatic), and halo(C₁₋₄aliphatic), wherein each of the foregoing C₁₋₄ aliphatic groups of R* isunsubstituted, wherein said disease, condition, or disorder is allergy,asthma, chronic obstructive pulmonary disease (COPD), diabetes,osteoarthritis, rheumatoid arthritis, Alzheimer's disease, Huntington'sdisease, Parkinson's disease, AIDS-associated dementia, amyotrophiclateral sclerosis (AML), multiple sclerosis (MS), schizophrenia,cardiomyocyte hypertrophy, perivascular fibrosis, benign prostatichyperplasia, vascular smooth muscle cell proliferation, endothelialdysfunction, ischemia/reperfusion-induced injury, stroke, baldness,cancer, malignoma, hepatomegaly, hypertension, cardiovascular disease,cardiomegaly, cystic fibrosis, restenosis, psoriasis, inflammation,hypertension, angina pectoris, cerebrovascular contraction, peripheralcirculation disorder, premature birth, preterm labor, atherosclerosis,vasospasm, cerebral vasospasm, coronary vasospasm, retinopathy, neuriteoutgrowth, glaucoma, erectile dysfunction (ED), AIDS, a respiratorysyncytial viral (RSV) infection, osteoporosis, Crohn's Disease, colitis,or Raynaud's Disease.
 25. The method of claim 24, wherein the compoundis represented by the formula (I-b) or a pharmaceutically acceptablesalt thereof:

wherein each of R^(H2), R^(H3), R^(H4), R^(H5), and R^(H6) is,independently, hydrogen, halogen, —CN, —NO₂, —OR, —B(OR)₂, —OC(O)R,—OC(O)OR, —OC(S)R, —SR, —SC(O)R, —SC(S)R, —C(O)OR, —C(O)NRR′, —C(S)NRR′,—NRR′, —S(O)R, —S(O)₂R, —S(O)₂NRR′, optionally substituted C₁₋₄haloaliphatic, C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl, 3- to8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclicheterocyclyl, or 5- to 8-membered monocyclic heteroaryl, 8- to12-membered bicyclic heteroaryl; and each of R and R′ is, independently,hydrogen, optionally substituted C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic,C₆₋₁₀ aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-memberedbicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to12-membered bicyclic heteroaryl.
 26. The method of claim 25, whereinR^(H4) is —OR, —B(OR)₂, —OC(O)R, —OC(O)OR, or —OC(S)R; each of R^(B4),R^(B5), and R^(B6) is hydrogen; and X² is N or C—H.
 27. The method ofclaim 26, wherein R^(H4) is —OH.
 28. The method of claim 24, wherein Wis —N(R^(F))—.
 29. The method of claim 24, wherein at least one of R^(G)or R^(H) is not hydrogen.
 30. The method of claim 29, wherein R^(H) isan optionally substituted C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀aryl, 3- to 8-membered monocyclic heterocyclyl, or 5- to 8-memberedmonocyclic heteroaryl.
 31. The method of claim 30, wherein R^(H) is anoptionally substituted C₆₋₁₀ aryl or 5- to 8-membered monocyclicheteroaryl.
 32. The method of claim 31, wherein the compound isrepresented by formula (II-d) or a pharmaceutically acceptable saltthereof:

wherein R^(F) is hydrogen, optionally substituted C₁₋₆ aliphatic, C₁₋₄haloaliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl, 3- to 8-memberedmonocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl;each of R^(H2), R^(H3), R^(H4), R^(H5), and R^(H6) is, independently,hydrogen, halogen, —CN, —NO₂, —OR, —B(OR)₂, —OC(O)R, —OC(O)OR, —OC(S)R,—SR, —SC(O)R, —SC(S)R, —C(O)OR, —C(O)NRR′, —C(S)NRR′, —NRR′, —S(O)R,—S(O)₂R, —S(O)₂NRR′, optionally substituted C₁₋₄ haloaliphatic, C₁₋₆aliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl, 3- to 8-membered monocyclicheterocyclyl, 8- to 12-membered bicyclic heterocyclyl, or 5- to8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl;and each of R and R′ is, independently, hydrogen, optionally substitutedC₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, C₆₋₁₀ aryl, 3- to 8-memberedmonocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to8-membered monocyclic heteroaryl, or 8- to 12-membered bicyclicheteroaryl.
 33. The method of claim 32, wherein R^(H4) is —OR, —B(OR)₂,—OC(O)R, —OC(O)OR, or —OC(S)R; each of R^(B4), R^(B5), and R^(B6) ishydrogen; and X² is N or C—H.
 34. The method of claim 33, wherein R^(H4)is —OH.
 35. The method of claim 34, wherein the compound is representedby formula (II-f) or (II-g), or a pharmaceutically acceptable saltthereof:


35. The method of claim 34, wherein each of R^(B4), R^(B5), R^(B6), andR^(B7) is hydrogen.
 36. The method of claim 24, wherein each of R^(B4),R^(B5), and R^(B6) is hydrogen; X⁷ is N or C—H; X² is N or C—H; and eachof R^(B2), R^(B3), R^(H5), and R^(H6) is, independently, hydrogen,halogen, —CN, —NO₂, —OR, —B(OR)₂, —OC(O)R, —OC(O)OR, —C(O)OR, —C(O)NRR′,—C(S)NRR′, —NRR′, —S(O)₂R, —S(O)₂NRR′, optionally substituted C₁₋₄haloaliphatic, C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, wherein each of Rand R′ is, independently, hydrogen or optionally substituted C₁₋₆aliphatic.
 37. The method of claim 24, wherein the compound is any oneof the following compounds or a pharmaceutically acceptable saltthereof: